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									                                               77314                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               paragraph (f) of this AD, before further                DEPARTMENT OF HEALTH AND                              comment period) for comments to be
                                               flight, replace the existing bolts that                 HUMAN SERVICES                                        submitted and does not plan to extend
                                               attach the exhaust nozzle to the aft                                                                          the comment period beyond this date.
                                               engine flange with new improved bolts,                  Food and Drug Administration                          Please see section XV of this document
                                               in accordance with part B of the                                                                              for the proposed effective and
                                               Accomplishment Instructions of                          21 CFR Parts 201 and 343                              compliance dates of any final rule that
                                               Bombardier Service Bulletin 601R–78–                    [Docket No. 1977N–0094L]
                                                                                                                                                             may publish based on this proposal.
                                               021, dated June 2, 2006. Accomplishing                                                                        ADDRESSES: You may submit comments,
                                                                                                       RIN 0910–AF36                                         identified by Docket No. 1977N–0094L
                                               the bolt replacement for an engine
                                               exhaust nozzle terminates the repetitive                                                                      and Regulatory Information Number
                                                                                                       Internal Analgesic, Antipyretic, and
                                               inspections required by paragraph (f) of                                                                      (RIN) 0910–AF36 by any of the
                                                                                                       Antirheumatic Drug Products for Over-                 following methods:
                                               this AD for that engine exhaust nozzle                  the-Counter Human Use; Proposed                       Electronic Submissions
                                               only.                                                   Amendment of the Tentative Final                         Submit electronic comments in the
                                                 Note 2: Bombardier Service Bulletin 601R–             Monograph; Required Warnings and                      following ways:
                                               78–021, dated June 2, 2006, refers to Short             Other Labeling                                           • Federal eRulemaking Portal: http://
                                               Brothers Service Bulletin CF34–NAC–78–                  AGENCY:    Food and Drug Administration,              www.regulations.gov. Follow the
                                               024, Revision 4, dated November 10, 2005, as            HHS.                                                  instructions for submitting comments.
                                               an additional source of service information                                                                      • Agency Web site: http://
                                               for accomplishment of the replacement.
                                                                                                       ACTION:   Proposed rule.                              www.fda.gov/dockets/ecomments.
                                                                                                       SUMMARY: The Food and Drug                            Follow instructions for submitting
                                               Terminating Action                                      Administration (FDA) is proposing to                  comments on the agency Web site.
                                                                                                                                                             Written Submissions
                                                  (h) Within 4,000 flight hours after the              amend its over-the-counter (OTC)
                                                                                                                                                                Submit written submissions in the
                                                                                                       labeling regulations and the tentative
                                               effective date of this AD: For the left and                                                                   following ways:
                                                                                                       final monograph (TFM) for OTC internal                   • FAX: 301–827–6870.
                                               right engine exhaust nozzles, replace the
                                                                                                       analgesic, antipyretic, and                              • Mail/Hand delivery/Courier [For
                                               existing bolts that attach the exhaust                  antirheumatic (IAAA) drug products to
                                               nozzle to the aft engine flange with new,                                                                     paper, disk, or CD–ROM submissions]:
                                                                                                       include new warnings and other                        Division of Dockets Management (HFA–
                                               improved bolts, in accordance with part                 labeling requirements advising
                                               B of the Accomplishment Instructions of                                                                       305), Food and Drug Administration,
                                                                                                       consumers about potential risks and                   5630 Fishers Lane, rm. 1061, Rockville,
                                               Bombardier Service Bulletin 601R–78–                    when to consult a doctor. FDA is also                 MD 20852.
                                               021, dated June 2, 2006. Accomplishing                  proposing to remove the alcohol                          To ensure more timely processing of
                                               the replacement for the left and right                  warning in its regulations and add new                comments, FDA is no longer accepting
                                               engine exhaust nozzles terminates all of                warnings and other labeling for all OTC               comments submitted to the agency by e-
                                               the inspections required by paragraph                   IAAA drug products. The new labeling                  mail. FDA encourages you to continue
                                               (f) of this AD.                                         would be required for all OTC drug                    to submit electronic comments by using
                                                                                                       products containing an IAAA active                    the Federal eRulemaking Portal or the
                                               Alternative Methods of Compliance
                                                                                                       ingredient whether marketed under an                  agency Web site, as described in the
                                               (AMOCs)
                                                                                                       OTC drug monograph or an approved                     Electronic Submissions portion of this
                                                 (i)(1) The Manager, New York Aircraft                 new drug application (NDA). FDA is                    paragraph.
                                               Certification Office, FAA, has the                      issuing this proposal as part of its                     Instructions: All submissions received
                                               authority to approve AMOCs for this                     ongoing review of OTC drug products                   must include the agency name and
                                               AD, if requested in accordance with the                 after considering the advice of its                   Docket No. and RIN for this rulemaking.
                                               procedures found in 14 CFR 39.19.                       Nonprescription Drugs Advisory                        All comments received may be posted
                                                                                                       Committee (NDAC) and other available                  without change to http://www.fda.gov/
                                                 (2) Before using any AMOC approved                    information. FDA is proposing these                   ohrms/dockets/default.htm, including
                                               in accordance with § 39.19 on any                       labeling changes because it has                       any personal information provided. For
                                               airplane to which the AMOC applies,                     tentatively concluded they are necessary              additional information on submitting
                                               notify the appropriate principal                        for these ingredients to be considered                comments, see the ‘‘Comments’’ heading
                                               inspector in the FAA Flight Standards                   generally recognized as safe and                      of the SUPPLEMENTARY INFORMATION
                                               Certificate Holding District Office.                    effective and not misbranded for OTC                  section of this document.
                                                                                                       use. FDA will address information about                  Docket: For access to the docket to
                                               Related Information
                                                                                                       the cardiovascular risks of nonsteroidal              read background documents or
                                                 (j) Canadian airworthiness directive                  anti-inflammatory drugs (NSAIDs) that                 comments received, go to http://
                                               CF–2006–19, dated July 28, 2006, also                   was discussed at a February 16–18,                    www.fda.gov/ohrms/dockets/
                                               addresses the subject of this AD.                       2005, FDA advisory committee meeting,                 default.htm and insert the docket
                                                                                                       and the ‘‘Allergy alert’’ warning for                 number(s), found in brackets in the
                                                 Issued in Renton, Washington, on                      NSAID products, in a future issue of the              heading of this document, into the
                                               December 14, 2006.                                      Federal Register.                                     ‘‘Search’’ box and follow the prompts
                                               Stephen P. Boyd,                                        DATES: Submit written or electronic                   and/or go to the Division of Dockets
                                               Acting Manager, Transport Airplane                      comments, including comments on                       Management, 5630 Fishers Lane, rm.
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                                               Directorate, Aircraft Certification Service.            FDA’s economic impact determination,                  1061, Rockville, MD 20852.
                                               [FR Doc. E6–22043 Filed 12–22–06; 8:45 am]              by May 25, 2007. The specified                        FOR FURTHER INFORMATION CONTACT:
                                               BILLING CODE 4910–13–P                                  comment period is longer than is                      Marina Chang, Center for Drug
                                                                                                       normally provided for proposed rules.                 Evaluation and Research, Food and
                                                                                                       Because of the complexity of the                      Drug Administration, 10903 New
                                                                                                       proposed rule, FDA is providing an                    Hampshire Ave., Silver Spring, MD,
                                                                                                       additional 60 days (beyond the normal                 20993–0002, 301–796–2090.


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                           77315

                                               SUPPLEMENTARY INFORMATION:                              new warnings and other labeling for all               with publication of an expert panel
                                                                                                       OTC IAAA drug products. The proposed                  report and continued in 1988 with
                                               Table of Contents
                                                                                                       warnings and other labeling                           publication of the TFM. The
                                               I. Introduction                                         requirements will advise consumers of                 development of labeling for OTC IAAA
                                               II. Background                                          potential risks and when to consult a                 drug products is recorded in the
                                                  A. Development of OTC IAAA Drug                      doctor. More specifically, FDA is                     following documents.
                                                     Product Warnings                                  proposing the following changes to the
                                                  B. Completion of the OTC IAAA Drug                                                                         1. Warnings for Aspirin and
                                                                                                       labeling:
                                                                                                                                                             Acetaminophen
                                                     Products Final Monograph (FM)                        • Requiring a new liver warning for
                                               III. NDAC Meeting                                       products that contain acetaminophen.                     In the Federal Register of July 8, 1977
                                                  A. Data and Information Reviewed                        • Requiring a new stomach bleeding                 (42 FR 35346), FDA published the
                                                  B. Acetaminophen                                     warning for products that contain an                  report of the Advisory Review Panel on
                                                  C. Aspirin and Other NSAIDs                          NSAID (e.g., aspirin or ibuprofen).                   OTC Internal Analgesic, Antipyretic,
                                               IV. Additional Data and Information                        • Removing the alcohol warning                     and Antirheumatic Drug Products (the
                                               FDA Reviewed                                            currently required for all OTC IAAA                   IAAA Panel) for OTC IAAA active
                                                  A. Pre-existing Liver Disease as a Risk              drug products in § 201.322 (21 CFR                    ingredients: Acetaminophen, aspirin,
                                                     Factor for Acetaminophen                          201.322) and incorporating an alcohol                 carbaspirin calcium, choline salicylate,
                                                     Hepatotoxicity                                    warning in the new liver warning for                  magnesium salicylate, and sodium
                                                  B. Updated Literature about                          acetaminophen and the new stomach                     salicylate. The recommendations
                                                     Acetaminophen Toxicity                            bleeding warning for NSAIDs.                          included labeling and warnings for:
                                                  C. Aspirin and Other NSAIDs                             • Requiring that the ingredient                       • Aspirin: ‘‘Caution: Do not take this
                                               V. FDA’s Tentative Conclusions                          acetaminophen be prominently                          product if you have stomach distress,
                                                  A. Acetaminophen                                     identified on the product’s principal                 ulcers or bleeding problems except
                                                  B. Aspirin and Other NSAIDs                          display panel (PDP) of the immediate                  under the advice and supervision of a
                                               VI. FDA’s Proposal                                      container and the outer carton, if                    physician’’ (42 FR 35346 at 35387), and
                                                  A. Alcohol Warning                                   applicable.                                              • Acetaminophen: ‘‘Do not exceed
                                                  B. Acetaminophen                                        • Requiring that the name of the                   recommended dosage because severe
                                                  C. Aspirin and other NSAIDs                          NSAID ingredient followed by the term                 liver damage may occur’’ (42 FR 35346
                                                  D. Requirements to Supplement                        ‘‘NSAID’’ be prominently identified on                at 35415).
                                                     Approved Applications                             the product’s PDP of the immediate                       In the Federal Register of November
                                                  E. Regulatory Action                                 container and the outer carton, if                    16, 1988 (53 FR 46204), FDA published
                                                  F. Conforming Changes to the OTC                     applicable.                                           a tentative monograph with the
                                                     IAAA TFM                                             This new labeling would be required                following warnings for:
                                               VII. Additional Issues for Consideration                for all OTC drug products containing an                  • Aspirin: ‘‘Do not take this product
                                                  A. Safe and Effective Daily                          IAAA active ingredient, whether                       if you have stomach problems (such as
                                                     Acetaminophen Dose                                marketed under an OTC drug                            heartburn, upset stomach, or stomach
                                                  B. Daily Dose Recommendations for                    monograph or an approved NDA. FDA                     pain) that persist or recur, or if you have
                                                     Alcohol Abusers                                   bases this proposal on its reviews of the             ulcers or bleeding problems, unless
                                                  C. Combinations With Methionine or                   medical literature, data provided to                  directed by a doctor’’ (53 FR 46204 at
                                                     Acetylcysteine                                    FDA, and recommendations made by                      46256), and
                                                  D. Package Size and Configuration                    NDAC. FDA has tentatively concluded                      • Acetaminophen: ‘‘Prompt medical
                                                     Limitations                                       that new labeling for OTC IAAA drug                   attention is critical for adults as well as
                                                  E. Label Warning for Individuals With                products is necessary for the safe and                for children even if you do not notice
                                                     Human Immunodeficiency Virus                      effective use of these products by                    any signs or symptoms.’’ This warning
                                                     (HIV)                                             consumers.                                            follows the general overdose warnings
                                                  F. Drug Interactions Between                                                                               in 21 CFR 330.1(g) (53 FR 46204 at
                                                     Acetaminophen and Warfarin                        II. Background                                        46213).
                                               VIII. Legal Authority                                      FDA believes that acetaminophen and                2. Warnings in the Professional Labeling
                                                  A. Statement About Warnings                          NSAIDs, when labeled appropriately                    for Aspirin
                                                  B. Marketing Conditions                              and used as directed, are safe and
                                               IX. Voluntary Implementation                            effective OTC drug products that benefit                 In the Federal Register of October 23,
                                               X. Analysis of Impacts                                  tens of millions of consumers every                   1998 (63 FR 56802), FDA published
                                                  A. Need for the Rule                                 year. FDA believes that these products                labeling for health professionals (not
                                                  B. Impact of the Rule                                should continue to be accessible to                   available in OTC drug product labeling)
                                                  C. Impact on Affected Sectors                        consumers in the OTC setting.                         that provided for cardiovascular and
                                                  D. Alternatives                                         • Internal analgesics have long been               rheumatologic indications. The labeling
                                                  E. Benefits                                          very effective OTC drug products for the              listed adverse reactions reported in the
                                               XI. Paperwork Reduction Act of 1995                     intermittent treatment of minor aches                 literature, e.g., hypotension (low blood
                                               XII. Environmental Impact                               and pains and fever.                                  pressure); tachycardia (rapid heart rate);
                                               XIII. Federalism                                           • At their recommended OTC doses,                  dizziness; headache; dyspepsia
                                               XIV. Request for Comments                               these products are only rarely associated             (indigestion); bleeding, ulceration, and
                                               XV. Proposed Effective and Compliance                   with serious adverse events relative to               perforation of the gastrointestinal (GI)
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                                               Dates                                                   the number of consumers who use these                 tract; nausea; and vomiting. FDA
                                               XVI. References                                         products.                                             determined that consumers were not
                                                                                                                                                             able to determine when they needed to
                                               I. Introduction                                         A. Development of OTC IAAA Drug                       take aspirin to prevent cardiovascular
                                                 FDA is proposing to: (1) Amend the                    Product Warnings                                      events, such as stroke, myocardial
                                               TFM for OTC IAAA drug products, (2)                       The development of a monograph for                  infarction (damage to the heart muscle),
                                               remove the alcohol warning, and (3) add                 OTC IAAA drug products began in 1977                  or other conditions. FDA did not


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                                               77316                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               consider it possible to provide adequate                   Ask a doctor before use if you have:               2. Aspirin and Other NSAIDs—GI
                                               directions and warnings to enable the                      • Problems or serious side effects                 Bleeding and Renal Toxicity
                                               layperson to make a reasonable self-                    from taking pain relievers or fever
                                               diagnosis of these cardiovascular and                                                                            Aspirin and other NSAIDs are
                                                                                                       reducers                                              available OTC for the treatment of minor
                                               rheumatologic conditions.
                                                                                                          • Stomach problems that last or come               aches and pain, for the treatment of
                                               3. Alcohol Warnings for Acetaminophen                   back, such as heartburn, upset stomach,               headaches, and for fever reduction. Per
                                               and NSAIDs                                              or pain                                               aspirin’s professional labeling (not part
                                                  In the Federal Register of October 23,                  • Ulcers                                           of the OTC drug product labeling),
                                               1998 (63 FR 56789), FDA published a                                                                           aspirin may be used to reduce the risk
                                                                                                          • Bleeding problems                                of serious cardiovascular events when
                                               final regulation stating that any OTC
                                               drug product, labeled for adult use,                       • High blood pressure, heart or                    taken on a daily basis under the
                                               containing acetaminophen, aspirin,                      kidney disease, are taking a diuretic, or             direction of a physician. Aspirin is also
                                               carbaspirin calcium, choline salicylate,                are over 65 years of age.                             effective in treating a variety of
                                               ibuprofen, ketoprofen, magnesium                           FDA received several comments (Refs.               rheumatologic diseases under the
                                               salicylate, naproxen sodium, and                        1 and 2) about the proposed warning for               direction of a physician. The
                                               sodium salicylate must bear an alcohol                  kidney disease and reopened the                       professional labeling also includes
                                               warning statement in its labeling.                      administrative record on June 4, 2003                 information about the potential risk of
                                               Section 201.322 requires the following                  (68 FR 33429), to allow for additional                GI bleeding and renal toxicity associated
                                               statements:                                             public comment. FDA continues to                      with aspirin.
                                                  • For products containing                            propose a warning about kidney disease                   OTC nonaspirin salicylates include
                                               acetaminophen:                                          for ibuprofen and other NSAIDs in this                the NSAIDs ibuprofen, naproxen
                                                  Alcohol Warning: If you consume 3 or                 document. In a future issue of the                    sodium, and ketoprofen. The product
                                               more alcoholic drinks every day, ask                    Federal Register, we will publish our                 labels for these products are not
                                               your doctor whether you should take                     final decision about this warning and                 required to contain warnings about GI
                                               acetaminophen or other pain relievers/                  the proposed inclusion of ibuprofen in                bleeding and renal toxicity. These
                                               fever reducers. Acetaminophen may                       the monograph.                                        ingredients are, however, also available
                                               cause liver damage.                                                                                           by prescription at strengths higher than
                                                  • For products containing aspirin,                   B. Completion of the OTC IAAA Drug
                                                                                                                                                             in OTC products and the prescription
                                               carbaspirin calcium, choline salicylate,                Products FM
                                                                                                                                                             product labeling contains warnings
                                               ibuprofen, ketoprofen, magnesium                          In the process of completing the FM                 about these risks.
                                               salicylate, naproxen sodium, and                        for OTC IAAA drug products, FDA
                                               sodium salicylate:                                                                                            III. NDAC Meeting
                                                                                                       reviewed a variety of data regarding the
                                                  Alcohol Warning: If you consume 3 or                                                                         At a September 19 and 20, 2002,
                                                                                                       safety of acetaminophen, aspirin, and
                                               more alcoholic drinks every day, ask                                                                          meeting, NDAC considered products
                                                                                                       other NSAIDs. FDA continued to receive
                                               your doctor whether you should take                                                                           currently marketed with OTC IAAA
                                                                                                       serious adverse event reports associated
                                               (name of active ingredient) or other pain                                                                     ingredients, including acetaminophen,
                                                                                                       with the use of these products during
                                               relievers/fever reducers. (Name of active                                                                     aspirin, carbaspirin calcium, choline
                                                                                                       this review. These serious adverse
                                               ingredient) may cause stomach                                                                                 salicylate, ibuprofen, ketoprofen,
                                                                                                       events included unintentional
                                               bleeding.                                                                                                     magnesium salicylate, naproxen
                                                  • For products containing                            acetaminophen hepatotoxicity and
                                                                                                       NSAID-related GI bleeding and renal                   sodium, and sodium salicylate. FDA
                                               acetaminophen with other IAAA active
                                                                                                       toxicity. Although the occurrence of                  expressed its belief that these products
                                               ingredients:
                                                                                                       these events is rare, relative to the                 should remain available OTC given their
                                                  Alcohol Warning: If you consume 3 or
                                                                                                       extensive use of the products, as                     overall effectiveness and safety, the
                                               more alcoholic drinks every day, ask
                                                                                                       described in the text that follows, FDA               benefit to consumers of having a pain
                                               your doctor whether you should take
                                                                                                       believes that labeling changes are                    reliever and fever reducer available
                                               (insert acetaminophen and one other
                                                                                                       necessary for the safe and effective use              OTC, and the use of these products by
                                               IAAA active ingredient—including, but
                                                                                                       of these products and to reduce the                   tens of millions of people weekly. FDA
                                               not limited to aspirin, carbaspirin
                                                                                                       associated morbidity.                                 suggested that certain interventions
                                               calcium, choline salicylate, magnesium
                                                                                                                                                             could decrease the frequency and
                                               salicylate, or sodium salicylate) or other              1. Unintentional Acetaminophen                        morbidity of these serious adverse
                                               pain relievers/fever reducers.                          Hepatotoxicity                                        events. NDAC members were asked to
                                               Acetaminophen and (insert name of one
                                                                                                         Acetaminophen is widely available in                consider which additional interventions
                                               other IAAA active ingredient—
                                                                                                       numerous single ingredient and                        were necessary to reduce the occurrence
                                               including, but not limited to aspirin,
                                                                                                       combination OTC drug products, and in                 of serious adverse events. The
                                               carbaspirin calcium, choline salicylate,
                                                                                                       many prescription drug products, as a                 presentations made at the meeting, and
                                               magnesium salicylate, or sodium
                                                                                                       pain reliever and/or fever reducer. OTC               NDAC’s findings, are summarized in
                                               salicylate) may cause liver damage and
                                                                                                       acetaminophen drug products, as                       this document. More information about
                                               stomach bleeding.
                                                                                                       currently labeled and used, have been                 the September 2002 NDAC meeting is
                                               4. Proposed Amendment to Include                        reported to be associated with                        available on the Internet and in the
                                               Ibuprofen as a Generally Recognized                     unintentional overdose that may lead to               Division of Dockets Management (see
                                               Safe and Effective OTC IAAA Active                                                                            ADDRESSES).
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                                                                                                       serious hepatotoxicity (Ref. 3). The
                                               Ingredient                                              IAAA Panel discussed overdose-related                 A. Data and Information Reviewed
                                                  In the Federal Register of August 21,                hepatotoxicity (42 FR 35346 at 35413 to
                                               2002 (67 FR 54139), FDA proposed to                     35414), and FDA addressed it in the                     FDA provided NDAC with the
                                               include ibuprofen in the monograph for                  IAAA TFM (53 FR 46204 at 46213 to                     following data and information (Ref. 3):
                                               OTC IAAA drug products with                             46218). (See section II.A.1 of this                     • Applicable sections of rulemakings
                                               additional warnings:                                    document.)                                            for OTC IAAA active ingredients.


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                            77317

                                                  • Proposed and final rules for the                     • Consumers are unaware of the risks                     • Adjustment of the maximum total
                                               alcohol warning for OTC IAAA drug                       of exceeding the recommended dose of                    daily dose or dosing interval
                                               products.                                               acetaminophen with a single product, or                    • Changes in labeling that identify the
                                                  • Final rule for professional labeling               of simultaneously using multiple                        population and highlight the risks
                                               of OTC drug products containing                         products containing acetaminophen.                         • Additional research on specific
                                               aspirin.                                                  FDA asked NDAC what additional                        subpopulations
                                                  • Amendment to propose inclusion of                  measures could be taken to better ensure                   • Consumer and physician education.
                                               ibuprofen in the monograph for OTC                      that prescribers and other people are                      FDA asked NDAC whether additional
                                               IAAA drug products.                                     aware of the potential risks associated                 studies are needed to evaluate these
                                                  • For acetaminophen, FDA reviews of                  with exceeding the recommended dose                     issues. FDA suggested a number of
                                               data, poisoning data in Toxic Exposure                  of prescription or OTC drug products                    subjects for potential research:
                                               Surveillance System (TESS), exposure                    containing acetaminophen and with                          • Evaluation of the effectiveness of
                                               data from poison control centers,                       using multiple products containing                      educational programs
                                               overdose reference articles, and an                     acetaminophen. FDA suggested the                           • Evaluation of revised labeling
                                               abstract describing trends in acute liver               following possible measures for OTC                        • Surveillance of serious
                                               failure in the United States.                           drug products:                                          acetaminophen hepatotoxicity cases
                                                  • For aspirin/NSAIDs, FDA reviews                      • Consumer education                                     • Enhanced collection of information
                                               of data and articles from the medical                     • Changes in labeling that identify                   when medication errors occur
                                                                                                       and highlight the risks
                                               literature.                                                                                                        • Better understanding of consumer
                                                                                                         • Packaging that may enhance
                                                  NDAC also considered submissions                                                                             use of these products.
                                                                                                       appropriate use
                                               and presentations from industry and                       • Consumer inserts.                                   2. Presentations and Submissions to
                                               individuals during the open public                        For prescription products, FDA                        NDAC
                                               sessions (Refs. 4 and 5).                               suggested:
                                                                                                         • Unit of use packaging with labeling                    As a lead-in to the liver toxicity
                                               B. Acetaminophen
                                                                                                       on each blister pack                                    discussion, Dr. William Lee, of the
                                                 On the first day of the meeting                         • Physician and pharmacist                            University of Texas Southwestern
                                               (September 19, 2002), NDAC considered                   education                                               Medical Center at Dallas, presented the
                                               safety issues related to the use of                       • Publication of information in                       results of acute liver failure (ALF)
                                               acetaminophen, unintentional overdose,                  professional journals                                   studies in the United States (Ref. 6). He
                                               and the potential for hepatotoxicity                      • Consumer education                                  estimated that between 1,000 and 2,000
                                               from both OTC and prescription                            • FDA publications to identify and                    ALF cases occur in the United States
                                               acetaminophen products.                                 highlight the danger and risk                           each year and are associated with high
                                               1. Points for Discussion                                  • Providing patient information                       mortality. Dr. Lee conducted a
                                                                                                       leaflets and stickers when dispensing                   retrospective analysis of 177 cases of
                                                 FDA asked NDAC to discuss possible                    the prescription.                                       ALF reported in the literature between
                                               factors that might contribute to                          FDA also asked NDAC if there are                      1986 and 1998. Of these, 20 percent
                                               unintentional overdose (Ref. 3) and                     identifiable factors that might make                    were attributed to acetaminophen
                                               provided the following points for                       some individuals more susceptible to                    toxicity. To study ALF prospectively,
                                               consideration:                                          hepatic toxicity (e.g., underlying liver                Dr. Lee also formed a study group of 25
                                                 • Acetaminophen is available to                       disease, malnutrition, drug interactions,               treatment centers in 1998. Details of the
                                               consumers in many OTC and                               and alcohol users). If subpopulations at                group’s initial 308 cases are presented
                                               prescription drug products (i.e., single                increased risk of acetaminophen-                        in table 1. Approximately 40 percent of
                                               ingredient and combinations with                        induced hepatotoxicity could be                         the cases were due to acetaminophen
                                               various other active ingredients).                      identified, FDA asked NDAC what                         toxicity, which was increased when
                                                 • Consumers fail to identify                          reasonable measures could be taken to                   compared to the rate of acetaminophen
                                               acetaminophen as an ingredient in their                 decrease their risk. FDA suggested some                 toxicity in the cohort from Dr. Lee’s
                                               OTC and prescription drug products.                     possible measures:                                      retrospective analysis.

                                                                                        TABLE 1.— STUDY GROUP SERIES OF ALF CASES (N = 308)
                                                                                                                                                ALF Etiology

                                                         Case Report Data                                                                                                        All Other
                                                                                           Acetaminophen Induced          Drug (Not Acetaminphen)              Indeterminate     Causes        P value
                                                                                                  (n=120)                     Induced (n=40)                   Cause (n=53)       (n=95)

                                                 Sex (% Female)                                                   79                               73                     60            72      NS*

                                                 Age (years)                                                      36                               41                     38            43        0.02

                                                 Jaundice (days)                                                   1                               12                     12             4       <0.001

                                                 Coma (%)                                                         50                               43                     47            47       NS
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                                                 Alanine aminotransferase (ALT)
                                                   (International Units/Liter (IU/
                                                   L))**                                                       4310                               574                    947         1060        <0.001

                                                 Bilirubin                                                         4.3                             20.2                   24.5          12.6     <0.001




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                                               77318                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                                                              TABLE 1.— STUDY GROUP SERIES OF ALF CASES (N = 308)—Continued
                                                                                                                                                 ALF Etiology

                                                         Case Report Data                                                                                                             All Other
                                                                                           Acetaminophen Induced          Drug (Not Acetaminphen)               Indeterminate         Causes            P value
                                                                                                  (n=120)                     Induced (n=40)                    Cause (n=53)           (n=95)

                                                 Transplant (%)                                                    6                                  53                     51              36           <0.001

                                                 Spontaneous survival (%)                                         68                                  25                     17              33           <0.001

                                                 Overall survival (%)                                             73                                  70                     64              61          NS
                                                  * Not significant ** ALT (normal range 0–35 IU/L)


                                                 Of the 120 acetaminophen toxicity                     acetaminophen prescription products                      accidental (ingestion of drugs for pain
                                               cases identified in Dr. Lee’s series, 12                and OTC acetaminophen products at the                    relief, without suicidal intent) and
                                               were omitted due to concomitant                         same time, some for as long as 2 to 3                    suicidal (ingestion with admitted
                                               patient issues that would have                          months. In 70 percent of the cases,                      suicidal attempt) ingestion. The type of
                                               confounded the analysis. The remaining                  patients ingested more than 4 grams (g)                  ingestion could not be determined in 5
                                               108 cases were analyzed and showed                      of acetaminophen per day                                 cases, resulting in a comparison of 103
                                               that alcohol use was reported in 57                     (recommended maximum daily dose),                        cases (table 2). More than half of the
                                               percent of the cases and alcohol abuse                  and 32 percent of the cases reported                     acetaminophen toxicity cases (57
                                               was reported in 19 percent of the cases.                ingestion of more than 10 g per day.                     percent) were accidental.
                                               Individuals in 38 percent of the cases                     A comparison was conducted among
                                               were taking both narcotic-                              the 108 cases of toxicity due to

                                                                                     TABLE 2.—SUICIDAL VS. ACCIDENTAL ACETAMINOPHEN ALF CASES
                                                                                                                         Accidental (n=59)                 Suicidal (n=44)                    p-value

                                                 Age                                                                                            39                              33                        0.011

                                                 Acetaminophen total (g)                                                                        20                              29                      NS

                                                 Antidepressant                                                                            36%                             34%                          NS

                                                 Alcohol (non-abuse use)                                                                   55%                             61%                          NS

                                                 Double use*                                                                               24%                               5%                           0.02

                                                 Narcotic/acetaminophen                                                                    54%                             14%                            0.001

                                                 ALT (IU/L)                                                                              3,616                            5,929                          <0.001

                                                 Creatine                                                                                       2.5                             1.3                       0.008

                                                 Survival                                                                                  71%                             75%                          NS
                                                  * Use of more than one acetaminophen containing product.


                                                  The incidence of use of                              databases were used to estimate the                        4. Multiple Cause of Death Files—a
                                               antidepressants and alcohol was nearly                  occurrence of these events:                              data file that contains information from
                                               identical in the accidental and suicidal                  1. National Hospital Ambulatory Care                   death certificates.
                                               groups. The accidental cases included a                 Survey: Emergency Department (ED)                          Acetaminophen overdose
                                               larger percentage of subjects who                       Component—a probability survey                           (unintentional and intentional) was
                                               double-dosed or used a narcotic/                                                                                 associated with an annual average of
                                                                                                       sampling of visits made to emergency
                                               acetaminophen combination product.                                                                               over 56,000 emergency department
                                                                                                       departments and short stay hospitals in
                                               Survival rates were also similar. Lee                                                                            visits (1993 to 1999) and more than
                                               concluded that acetaminophen toxicity                   the United States.
                                                                                                                                                                26,000 hospitalizations (1990 to 1999).
                                               accounted for about a third of all deaths                 2. National Electronic Injury                          Between 1996 and 1998, an annual
                                               from ALF in this case series and appears                Surveillance System—collects                             average of 458 deaths was attributed, at
                                               to be a growing problem in the United                   information on consumer product-                         least in part, to acetaminophen
                                               States.                                                 related injuries treated in emergency                    overdose. Unintentional acetaminophen
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                                                  FDA staff presented a safety analysis                departments of 66 selected hospitals.                    overdose was associated with an annual
                                               of hepatotoxicity associated with                         3. National Hospital Discharge                         average of over 13,000 emergency
                                               acetaminophen (Ref. 7). The cases were                  Survey—a probability survey sampling                     department visits (1993 to 1999), 2,189
                                               reported as ‘‘intentional overdose’’ and                of patient discharge records from non-                   hospitalizations (1990 to 1999), and 100
                                               ‘‘unintentional overdose.’’ The reported                Federal, short stay hospitals in the                     deaths (1996 to 1998). Each event in
                                               doses were rarely within the                            United States.                                           these tallies is independent from the
                                               recommended range. Four national                                                                                 others. No information about associated


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                                                                     Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                               77319

                                               hepatotoxicity was available for these                  containing acetaminophen are available                 emergency department visits are most
                                               cases. FDA reviewed the age                             for different age groups. The age                      prevalent among young people, this age
                                               distribution for acetaminophen                          distribution of unintentional overdose                 group accounts for the lowest
                                               overdoses. Medication use varies by age                 cases varies among reporting databases                 percentage of cases of mortality.
                                               and different OTC drug products                         and is shown in table 3. While

                                                                                           TABLE 3.—AGE DISTRIBUTION OF UNINTENTIONAL CASES
                                                                                                                                                          Age (years)

                                                                                                                              <17                           17—64                            >65

                                                 Emergency department visit                                                                74%                             25%                             <1%

                                                 Hospitalization                                                                           23%                             70%                             7%

                                                 Mortality                                                                                 1%                              75%                             23%



                                                 Chronic liver disease has been                        acetaminophen. Using the multiple                      unintentional and intentional overdose
                                               postulated to be one of the factors that                cause of death database, the presence of               with mortality outcomes was examined
                                               increases the risk of hepatotoxicity from               chronic liver disease among cases of                   (table 4).

                                               TABLE 4.—PERCENT OF LIVER DISEASE REPORTED AMONG FATAL ACETAMINOPHEN OVERDOSE CASES, MORTALITY DATA,
                                                                                            1996–1998
                                                                             Liver Disease Reported                                             Unintentional (N=235)              Intentional (N=1,010)

                                                 Chronic alcoholic                                                                                                      13%                                1%

                                                 Other chronic liver disease                                                                                            48%                                8%



                                                  These findings suggest that chronic                     FDA also presented an analysis of                   hepatologists and other practitioners.
                                               liver disease, in the presence or absence               cases of hepatotoxicity associated with                One case series was obtained
                                               of alcohol, may be a risk factor for                    acetaminophen from the published                       exclusively from a consortium of liver
                                               developing or increasing severity of                    literature. A MEDLINE search identified                transplant centers. The number of cases
                                               hepatotoxicity among people with                        all U.S. case series containing at least 10            per series ranged from 47 to 73. Two
                                               unintentional overdose. However, this                   cases that had been published in the                   case series were largely pediatric, and
                                               analysis has limitations. If the presence               previous 10 years (Ref. 7). Eight case                 the remaining six case series consisted
                                               of alcohol or alcohol use was not                       series were identified, four of which                  of largely adult populations. Six of the
                                               mentioned on the death certificate,                     were derived exclusively from review of                case series reported gender, and in all
                                               alcohol related liver disease may be                    hospital medical charts. In two series,
                                                                                                                                                              six there was a preponderance of
                                                                                                       cases were obtained from hospitals,
                                               misclassified as other chronic liver                                                                           females. Intentionality was reported in
                                                                                                       published cases, the FDA adverse event
                                               disease. In addition, suicide cases may                 reporting system, and poison control                   five of the series. Table 5 shows the
                                               be misclassified as unintentional                       center databases. One case series was                  acetaminophen dose reported among in
                                               overdose to protect privacy.                            from a registry of cases reported by                   the unintentional overdose groups.

                                                                                 TABLE 5.—HEPATOTOXICITY SERIES: UNINTENTIONAL TOXICITY CASES
                                                                                                                                                                                 No. of Cases With Typical
                                                                   Case Series                      Reported Daily Doses (g/day)                No. of Cases in Series            Daily Dose of ≤4g/day

                                                 Johnston                                                                      1.3–20                                    53                                   9

                                                 Schiodt                                                                          2–30                                   21                                   3

                                                 Zimmerman                                                               ‘‘<4’’–‘‘>15’’*                                 67                                  27

                                                 Whitcomb                                                                      3.5–25                                    21                            None

                                                 Broughan                                                                15.9 (mean)                                       8                           None
                                                  * Dose was reported categorically.
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                                                 Nine people in the Johnston case                      the recommended dose, while 13 people                  in one case and 4 to 6 g/day in two
                                               series and three people in the Schiodt                  used between 4.1 and 6 g/day. In the                   cases). In the Broughan case study, none
                                               case series ingested 4 g/day or less of                 Whitcomb case series, 3 people used                    of the people took acetaminophen at the
                                               acetaminophen. In the Zimmerman case                    acetaminophen at, or slightly above, the               recommended dose.
                                               series, 27 people used acetaminophen at                 recommended dose (i.e., 3.5 to 5 g/day



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                                               77320                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                                 Table 6 compares the number of                        Intentionality could only be compared                 outcomes were defined as hepatic coma,
                                               deaths and serious outcomes for the                     in the adult case series. Serious                     acute liver failure, and liver transplant.
                                               unintentional and intentional groups.

                                                     TABLE 6.—COMPARISON OF UNINTENTIONAL AND INTENTIONAL TOXICITY GROUPS: CASES OF DEATH OR SERIOUS
                                                                                                OUTCOME
                                                                                     Case Series                                                   Unintentional                   Intentional

                                                 Johnston                                                                                                             17/53                       NA*

                                                 Schiodt                                                                                                              11/21                       4/50

                                                 Zimmerman                                                                                                            13/67                       NA*

                                                 Whitcomb                                                                                                              5/21                      NR**

                                                 Broughan                                                                                                               2/8                       0/40
                                                  *NA: Not applicable; **NR: Not reported


                                                  FDA also presented case data from the                acetaminophen product simultaneously.                 concentrated drops containing
                                               TESS of the American Association of                     These AAPCC data may underreport the                  acetaminophen 100 mg/milliliter (mL)
                                               Poison Control Centers (AAPCC). At                      actual number of acetaminophen                        were reportedly ingested in seven cases.
                                               that time, AAPCC had a repository of                    toxicity cases, because serious cases that               In 20 of the pediatric cases, 1 or more
                                               over 27 million human poison                            go directly to emergency departments,                 medication errors were reported. In
                                               exposures reported by over 60                           and chronic users of acetaminophen, are               three cases, the wrong product was
                                               participating centers. These centers                    unlikely to generate poison control                   used, i.e., the concentrated drops
                                               covered over 90 percent of the U.S.                     center contacts.                                      instead of the children’s acetaminophen
                                               population. Examination of AAPCC’s                         FDA staff reviewed spontaneous                     liquid formulation. In four cases,
                                               annual reports from 1995 to 1999 of                     reports of hepatoxicity in FDA’s adverse              incorrect measuring devices were used,
                                               cases listing acetaminophen as the                      event reporting system (AERS). U.S.                   i.e., teaspoonfuls instead of dropperfuls.
                                               primary (first) agent showed                            cases were identified that had been                   Five cases reported instances of
                                               acetaminophen to be the leading cause                   received by FDA between January 1998                  misinterpretation of labeled dosing
                                               of poisonings. In 1999, acetaminophen-                  and July 2001 and in which one or more                guidelines or misinterpretation of
                                               related calls represented 10 percent of                 acetaminophen containing products had                 instructions provided by a health care
                                               all calls to AAPCC. There was a                         been ingested. Of 633 reports, 43 were                provider.
                                               decrease in calls between 1995                          duplicates. Another 283 were excluded                    Sixty percent of the 282 adult cases
                                               (111,175) and 1999 (108,102). In 1999,                  for various reasons, primarily to exclude             (15 to 85 years old) were female and 229
                                               nearly 50 percent of the poison victims                 cases in which there was apparent                     required hospitalization. A total of 169
                                               associated with the calls received                      suicidal intent. A total of 307 cases were            adults experienced severe, life-
                                               treatment in health care facilities. Two                included in FDA’s analysis (25 pediatric              threatening liver injury; 124 of these
                                               percent of these victims were reported                  and 282 adult cases).                                 patients died and 7 required a liver
                                               to have developed major effects                            Pediatric cases (of children age 1 day             transplant. One hundred ninety-nine (71
                                               resulting from the poisoning, i.e., the                 to 8 years) consisted primarily of males              percent) adults reported using an
                                               signs or symptoms occurring as a result                 (approximately 70 percent), although                  acetaminophen product for a
                                               of acetaminophen exposure were life-                    gender was not reported in each case.                 therapeutic indication, primarily
                                               threatening or resulted in significant                  Fifteen of the 25 pediatric cases                     analgesia. In 74 (26 percent) cases, the
                                               residual disability. Fifty percent of the               involved severe, life-threatening liver               indication for use was unknown, and in
                                               calls involved children and adolescents                 injury. Of the 25 children, 10 died, 21               9 (3 percent) cases, abuse of a narcotic-
                                               (19 years of age or under). Of the                      were hospitalized, and 2 required only                acetaminophen prescription product
                                               acetaminophen related calls regarding                   treatment in an emergency department.                 was reported. One hundred thirty-eight
                                               children under 6 years of age                           The dose was estimated, based upon                    (38 percent) cases listed an unspecified
                                               (approximately 40,000 calls), 22 percent                reported daily doses and weight, in 10                acetaminophen product (unknown
                                               occurred in children who ingested adult                 cases to be 106 to 375 milligrams/                    whether single ingredient or
                                               formulations of acetaminophen.                          kilogram (mg/kg) per day. The                         combination product and whether OTC
                                                  In 1995, there were at least 76                      recommended pediatric dose is 75 mg/                  or prescription), 122 (33 percent) cases
                                               acetaminophen-related fatalities. By                    kg/day (Ref. 7). Twenty-two of the                    involved the use of a narcotic-
                                               1999, the number of acetaminophen-                      children (88 percent) took only 1                     acetaminophen prescription product,
                                               related fatalities increased to 141. Of                 product containing acetaminophen and                  and 76 (21 percent) cases reported use
                                               these, 92 (65 percent) were a result of                 3 children (12 percent) took 2 or more                of an OTC single ingredient
                                               suicidal intent, 43 (30 percent) were                   products containing acetaminophen.                    acetaminophen product. Approximately
                                               unintentional, and the dosing intent for                Sixteen of the cases (53 percent)                     25 percent of all adult cases reported
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                                               6 (4 percent) was undetermined. Among                   reported ingestion of a single ingredient             use of more than one acetaminophen
                                               the 43 unintentional fatalities, 28 (65                 acetaminophen product (APAP), 12                      product. When more than one
                                               percent) took one OTC drug product                      cases (40 percent) reported ingestion of              acetaminophen product was reported, a
                                               containing only acetaminophen; 4 (9                     an ‘‘unspecified APAP product’’ and the               narcotic-acetaminophen prescription
                                               percent) took one prescription product                  remainder of the cases reported                       product in combination with an OTC
                                               containing acetaminophen, and 11 (26                    ingestion of combination products. Of                 product containing acetaminophen was
                                               percent) took more than one                             the single ingredient products,                       used more often than any other


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                              77321

                                               combination of acetaminophen                            showed a mean and median daily dose                    reports was highly variable. Alcohol use
                                               products. These cases also used higher                  of 7.1 and 6.23 g, respectively. Twenty-               in these cases was defined by FDA as
                                               doses than people who took only one                     three of the 65 cases with severe liver                alcoholism or alcohol abuse in 64 cases;
                                               acetaminophen-containing product.                       injury reported doses of less than 4 g/                regular, daily, or moderate use in 23
                                                 Dosing amounts were reported in 132                   day. People who used more than one                     cases; occasional use in 10 cases;
                                               of the 282 adult cases. The mean and                    acetaminophen product reported taking                  previous use in 6 cases; and 13 cases
                                               median daily dose were 6.5 and 5 g,                     higher doses than people who took a                    did not provide a description. Eighty-six
                                               respectively, but ranged from 650 mg to                 single product. Qualitative dosing                     (74 percent) of the 116 alcohol users
                                               30 g/day. Where the dosage strength was                 information was provided for an                        developed severe liver injury. For those
                                               known, 500 mg acetaminophen was                         additional 43 (15 percent) cases with
                                                                                                                                                              cases with acetaminophen dose
                                               reported most often. If a dose range was                terms such as ‘‘excessive doses’’ or
                                               reported in the case, the mid-point was                                                                        information, the mean dose associated
                                                                                                       ‘‘recommended doses.’’ Two out of three
                                               used in the analysis. If the strength was               of these cases suggest that greater than               with toxicity was lower for alcohol
                                               unknown, a 500-mg strength was                          recommended doses were used.                           users compared to nonalcohol users
                                               assumed. Dosing in the 65 adults with                      Alcohol use was reported in 116 of                  (table 7).
                                               severe liver injury from this group                     the adult cases and the content of the

                                                                                             TABLE 7.—ACETAMINOPHEN DOSE AND ALCOHOL USE
                                                         Category of Liver Disease (Developed Post-Acetaminophen)                           Alcohol Users (Mean Dose)           Non-Users (Mean Dose)

                                                 All (N=132)                                                                                                  5.6 g (N=53)                    6.9 g (N=79)

                                                 Severe only (N=65)                                                                                           6.0 g (N=38)                    8.6 g (N=27)



                                                 A history of prior liver disease, or                  the 70 cases with pre-existing liver                   liver injury) that reported dosing
                                               possible underlying liver disease, was                  disease, 49 percent (70 percent)                       information. The second row shows a
                                               reported in 70 cases. In at least 20 of                 developed severe liver injury. Table 8                 dose comparison in people who
                                               these cases, the pre-existing liver                     shows the dose that was associated with                experienced severe liver injury after
                                               disease was reportedly due to alcohol.                  liver injury for cases with and without                acetaminophen exposure.
                                               Twenty-three people reported a history                  pre-existing liver disease. The first row
                                               of, or possible, viral hepatitis. Among                 includes all cases (all degrees of acute

                                                                                            TABLE 8.—ACETAMINOPHEN DOSE AND LIVER DISEASE
                                                                                                                                    Cases With Pre-existing Liver Dis-    Cases With No Pre-existing Liver
                                                   Category of Liver Injury Associated With Acetaminophen Dosing                          ease (Mean Dose)                    Disease (Mean Dose)

                                                 All (N=132)                                                                                              5.4 g (N=36)                        6.8 g (N=96)

                                                 Severe only (N=65)                                                                                       5.7 g (N=23)                        7.8 g (N=42)



                                                 Some additional factors may have                      provide certainty that acetaminophen                   identified and may have increased the
                                               contributed to the development of                       was the cause of any of the reported                   risk for hepatotoxicity.
                                               hepatotoxicity in these adults. Use of                  adverse event. Furthermore, incidence                     FDA presented NDAC with several
                                               other medications that may have                         rates cannot be determined, because the                questions that remained unaddressed by
                                               contributed to hepatotoxicity was                       numerator or denominator descriptors                   FDA’s review:
                                               reported in 93 cases, including 63 cases                for the entire population are not                         • Do users lack knowledge of the
                                               that involved products that are labeled                 available. Overall, spontaneous reports                potential for and symptoms of
                                               with warnings about potential                           may be subject to significant                          hepatotoxicity when using a product
                                               hepatotoxicity. A small number of                       underreporting.                                        containing acetaminophen?
                                               reports also mentioned the existence of                   The AERS cases strongly suggest that                    • Does malnutrition or fasting affect
                                               concomitant malnutrition or decreased                   particular circumstances were likely to                severity of hepatoxicity?
                                               oral intake.                                            have led to hepatotoxicity. Some                          • What is the contribution of
                                                 FDA noted that there are limitations                  examples of those circumstances follow:                concomitant hepatotoxic medication?
                                               to interpreting the AERS data. Dosing                     • Errors related to product confusion                   • What additional factors place a
                                               information may be unreliable.                          were mostly observed in pediatric cases.               small number of individuals at risk for
                                               Acetaminophen products are generally                    These errors primarily involved                        severe hepatotoxicity at various dose
                                               taken on an as-needed basis, so the                     confusion over varying product                         levels (i.e., under, at, or above the
                                               actual dose ingested can be difficult to                formulations and strengths and use of                  recommended dose)?
                                               ascertain. There is no certainty that all               inappropriate measuring devices.                          It is clear that unintentional
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                                               of the adult cases included in this                       • Many adults were taking more than                  acetaminophen doses are associated
                                               analysis were unintentional. Stigma                     the recommended dose of                                with a large number of emergency
                                               may be associated with reporting                        acetaminophen and, in some cases, use                  department and hospital admissions
                                               suicide, so cases may be reported as                    of multiple products likely contributed                and are related to an estimated 100
                                               unintentional when they were                            to hepatotoxicity.                                     deaths each year. Using a number of
                                               intentional overdoses. In addition,                       • Risk factors, such as alcohol use or               data sources, analyses have shown that
                                               spontaneous reporting systems cannot                    pre-existing liver disease, were                       circumstances leading to


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                                               77322                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               acetaminophen hepatotoxicity are                        acetaminophen reported by the AAPCC                   More patients were evaluated for
                                               multifactorial. FDA asked the committee                 is approximately 20 times that for                    transplants (11 versus 9), received
                                               to consider the contribution of each of                 ibuprofen.                                            transplants (2 versus 0), and died (3
                                               the following in producing                                 2 . Unintentional overdose of                      versus 0) as a result of unintentional
                                               unintentional overdose toxicity:                        acetaminophen can put consumers in a                  overdoses.
                                                  • Product—the ingredient is present                  life-threatening situation due to the                    3. Compared to the intentional
                                               in multiple prescription and OTC drug                   delayed onset of clinical symptoms of                 overdose group, the unintentional
                                               products and in multiple oral                           toxicity.                                             overdose group was more likely to have
                                               formulation strengths                                      3. Advertising portrays                            one or more of the following risk factors
                                                  • Knowledge—since a number of                        acetaminophen as a totally safe                       for acetaminophen toxicity: (1) Hepatic
                                               cases have occurred from multiple                       ingredient. This portrayal may                        disease, (2) acute or chronic alcohol use,
                                               product use and overuse, there is likely                exacerbate use and contribute to the                  (3) drug abuse, or (4) concomitant
                                               a lack of knowledge about safe use of                   silent danger resulting from overdose.                disease. Ninety-six percent of cases in
                                               acetaminophen                                              • One individual presented a review                the unintentional overdose group had
                                                  • Risk factors—multiple data sources                 of acetaminophen overdose admissions                  one or more of these risk factors, as
                                               identify alcohol and underlying liver                   at the University of Pennsylvania                     compared to 70 percent in the
                                               disease as risk factors that may increase               hospital over a 4-year period. Fifty-four             intentional group. Acute and chronic
                                               the potential for hepatotoxicity.                       reports of acetaminophen overdose were                alcohol use was present in 87 percent of
                                                  Several drug manufacturers and other                 found in the hospital’s database. Of the              unintentional overdose cases, as
                                               interested parties provided additional                  47 cases reviewed to date, 23 (50                     compared to 61 percent of the
                                               comment (Ref. 4):                                       percent) were reported to be                          intentional overdose cases. Thus, the
                                                  • One major manufacturer of                          unintentional overdoses. In 13 of these
                                                                                                                                                             existence of risk factors may have an
                                               acetaminophen OTC drug products                         23 cases, the reviewer was able to
                                                                                                                                                             impact on toxicity in unintentional
                                               provided the following comments:                        document that an attending physician or
                                                                                                                                                             ingestions.
                                                  1. The precise incidence of harmful,                 a psychiatry consultant concluded that
                                                                                                                                                                • One individual described the
                                               unintentional overuse cannot be                         there had been no suicidal intent.
                                                                                                          1. The median and average doses were               untimely death of her son who initially
                                               accurately determined from the current
                                                                                                       between 6 and 8 g/day. These values are               used a prescription product. When the
                                               databases. Forty-eight million American
                                                                                                       above the recommended maximum                         prescription was finished, he purchased
                                               adults use products containing
                                                                                                       daily dose (4 g/day), but below the 10                an OTC acetaminophen product and
                                               acetaminophen in any single week;
                                                                                                       to 15 g dosage usually considered to be               developed flu like symptoms. Another
                                               thus, harm is rare and is caused by
                                                                                                       toxic. There were three cases of                      OTC acetaminophen product was
                                               inadvertent overdose.
                                                  2. There are limitations to the AERS                 intentional overdose and three cases of               subsequently used to treat the flu
                                               data set for assessing hepatic events.                  unintentional overdose involving                      symptoms, resulting in hepatotoxicity.
                                               Patients consistently underestimate the                 prescription acetaminophen products.                  He was hospitalized and ultimately
                                               dose taken, and suicide attempts are                    OTC products were associated with 20                  died.
                                               often not recorded in patients who are                  intentional and 21 unintentional                         • A professional pharmaceutical
                                               found unconscious or intoxicated. The                   overdoses. More patients in the                       association encouraged consumers to
                                               AERS reports found to be definitely                     unintentional overdose group used                     carefully read product labeling. The
                                               associated with acetaminophen                           single ingredient acetaminophen (i.e.,                association also recommended: (1) Clear
                                               involved substantial overdose in                        not a combination product). The                       labeling on all prescription and OTC
                                               individuals with self-abusive behaviors                 primary reason reported for exceeding                 drug products containing
                                               (e.g., alcohol abuse, bulimia). Causality               the maximum dose was to treat                         acetaminophen with special statements
                                               cannot be ascertained using                             unrelieved pain. Many patients stated                 (e.g., ‘‘contains acetaminophen’’ on the
                                               retrospective data, especially case                     that they knew they were exceeding the                product’s PDP), and (2) pharmacists
                                               reports, because the dose history is often              recommended dose and did so because                   placing auxiliary labels on the vial of
                                               inaccurate.                                             they thought it was a safe drug. Thirty               prescription drug products containing
                                                  3. Formulations most commonly                        percent of the patients used the drug                 acetaminophen to identify this
                                               reported were OTC single-ingredient                     over a period of greater than 7 days.                 ingredient.
                                               and prescription combination                               2. The unintentional overdose group                   • A consumer public health
                                               acetaminophen products. OTC                             experienced greater morbidity and                     organization described a consumer
                                               acetaminophen combination products                      mortality than the intentional overdose               survey showing that many consumers
                                               were rarely reported.                                   group. The peak acetaminophen levels                  do not recognize the potential for harm
                                                  4. Serious hepatotoxicity occurs                     in the intentional overdose group were                from: (1) Taking more than the
                                               following substantial overdose (a single                much lower compared to the                            recommended dose, (2) taking more
                                               dose of approximately 15 g or use of                    unintentional overdose group (27.8                    than one product containing
                                               approximately 12 g for multiple days).                  versus 115.1 mg/L). The unintentional                 acetaminophen, or (3) inappropriately
                                                  5. FDA focused on unintentional                      overdose group had much higher peak                   combining OTC and prescription drug
                                               misuse. The manufacturer noted they                     levels of Alanine aminotransferase                    products containing acetaminophen.
                                               had implemented labeling changes to                     (ALT) (5,193 versus 3,065 units/L),                      • A member of a national health
                                               minimize the inadvertent overuse of                     Aspartate aminotransferase (AST) (6,819               foundation expressed concern that
                                               analgesics. The manufacturer                            versus 2,742 units/L), International                  present marketing practices make it very
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                                               recommended an organ specific                           Normalized Ratio (INR) (4 versus 2.5),                difficult to find the standard 325-mg
                                               overdose warning.                                       and total bilirubin (5.87 versus 1.87 mg/             acetaminophen dosage unit. As a result,
                                                  • One manufacturer of ibuprofen OTC                  dL). Patient outcomes were generally                  many consumers believe that the 500-
                                               drug products provided the following                    worse in the unintentional overdose                   mg product is the only one available.
                                               comments:                                               group, in which more patients failed to               This failure to more broadly market the
                                                  1. In overdose situations, in any given              have resolution of the liver problems                 lower dose may contribute to increased
                                               year, the number of deaths for                          from the overdose (31 versus 4 percent).              adverse events. The individual


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                           77323

                                               advocated educational efforts to help                   susceptibility to acetaminophen-                      (Ref. 5 Tab D). Consumers need to know
                                               minimize this problem.                                  associated hepatotoxicity at                          the type of medication and the dose of
                                                  • A spokesperson for a national                      unexpectedly low doses of                             OTC analgesic in every combination
                                               consumer organization described                         acetaminophen. The manufacturer                       product to ensure safe and effective use.
                                               marketing limitations that are employed                 provided arguments that the existence
                                               in the United Kingdom and intended to                                                                         3. NDAC Deliberations and
                                                                                                       of any of these factors in a case report
                                               limit the potential for overdose. In                                                                          Recommendations Concerning
                                                                                                       may each inherently interfere, for
                                               September 1998, a restriction was                                                                             Acetaminophen
                                                                                                       various reasons, with establishing the
                                               placed on the number of tablets in                      correct assessment of a hepatotoxic dose                 NDAC unanimously agreed that the
                                               acetaminophen packages for sale                         of acetaminophen.                                     evidence of risk associated with
                                               without a prescription. If sold in a                       • An expert panel sponsored by a                   unintentional overdose of
                                               supermarket, the maximum is 16 tablets                  manufacturer of acetaminophen                         acetaminophen warrants FDA labeling
                                               per package. If sold in a pharmacy, the                 products reviewed all 281 adult reports               changes, without awaiting the outcome
                                               maximum is 32 tablets per package.                      in AERS and assigned a probability                    of further studies. NDAC noted the
                                               There is also an overall restriction that               category relating the reported hepatic                following four major areas of concern:
                                               a maximum of 100 tablets can be                         adverse events to acetaminophen                          1. Unintentional use of multiple
                                               purchased at one time. The                              exposure. In 3 reports the adverse event              acetaminophen containing products
                                               representative stated that early                        and exposure were considered                             2. Exceeding the recommended dose
                                               evaluations of this program have shown                  ‘‘definitely’’ related, in 74 reports they            without recognizing the consequences
                                               decreases in (1) total and severe                       were ‘‘probably’’ related, 47 reports they               3. Improper dosing of infants
                                               acetaminophen overdoses and (2)                         were ‘‘possibly’’ related, in 53 reports                 4. The unknown consequences of use
                                               overdoses related to liver transplant and               they were unlikely to be related, and in              in special populations, such as alcohol
                                               death.                                                  27 reports they were definitely not                   abusers.
                                                  Several drug manufacturers and                       related. Data were considered                            NDAC recommended that the
                                               others submitted additional information                 insufficient in 73 reports, 3 reports were            minimum requirements for change
                                               for the committee to review (Ref. 5):                   not able to be evaluated and there was                should include, for all products
                                                  • One major manufacturer of                          no consensus regarding the evaluation                 containing acetaminophen (including
                                               acetaminophen OTC drug products                         of 1 report.                                          those available by prescription), the
                                               provided the following comments (Ref.                      Based on an assessment of several                  addition of distinctive labeling
                                               5, Tab A):                                              databases, a sponsor calculated that the              (highlighted or bold type) on the front
                                                  1. AERS serves as a signal generating                worst case scenario of deaths from                    panel or PDP to state that the products
                                               system for rare, unexpected adverse                     acetaminophen overdose is estimated to                contain acetaminophen. FDA noted that
                                               events in marketed products. It cannot                  be 213 deaths per year (Ref. 5, Tab A).               the nonproprietary name of prescription
                                               be used to determine event rates, dose                     • One manufacturer submitted an                    drugs must appear in labeling in letters
                                               ingested, or patient dosing intent.                     analysis of data from TESS (Ref. 5, Tab               at least half the size of the brand name
                                                  2. FDA’s review of the AERS data set                 B). The manufacturer made the                         (see 21 CFR 201.10(g)(2)). NDAC
                                               was intended to exclude obvious                         following conclusions from these data:                recommended that a similar provision
                                               suicide, usually associated with very                      1. The majority of hepatotoxicity                  also be applied to OTC drug products
                                               large drug ingestion. Thus, the reported                cases (65 percent of cases in the year                containing acetaminophen, such as a
                                               dosage (which could only be estimated                   2000) involved use of one                             standard to ensure prominence of
                                               in 48 percent of the reports in the data                acetaminophen-containing analgesic                    important information. NDAC stated
                                               set) is skewed significantly toward                     product.                                              that consumers need to be informed that
                                               labeled directions for use, so cases may                   2. Acetaminophen-containing cough/                 combining products containing
                                               falsely appear to be consistent with                    cold medications were not a significant               acetaminophen can result in exceeding
                                               inadvertent misuse.                                     contributor to the total number of                    the recommended dose.
                                                  3. The selective data in FDA’s AERS                  reports of acetaminophen associated                      NDAC commented that there are
                                               review cannot be used to determine an                   hepatotoxicity (2 percent of cases in the             insufficient data in the OTC setting on
                                               acetaminophen toxicity threshold                        year 2000).                                           risk management, understanding
                                               associated with any patient condition                      3. Only 1 percent of the reported cases            consumer behavior, and the
                                               (i.e., concomitant drug, alcohol history,               of hepatotoxicity in 2000 involved use                effectiveness of warnings on labels. This
                                               or pre-existing concomitant disease).                   of an OTC acetaminophen-containing                    lack of data makes it difficult to
                                                  4. The quality of the 281 adult reports              cough/cold product concomitantly with                 determine which factors contribute to
                                               in AERS was evaluated by the                            other acetaminophen-containing                        liver injury. Although these factors are
                                               manufacturer. The manufacturer                          product(s).                                           not clearly understood, NDAC
                                               concluded that 168 reports (24 percent)                    • One physician stated that 3 to 4 g               concluded that labeling revisions are
                                               contained insufficient information to                   of acetaminophen per day is the upper                 needed to help minimize any risks.
                                               estimate the dose taken and 212 reports                 range of a safe dose (Ref. 5 Tab C). For                 • Separate liver toxicity and alcohol
                                               (88 percent) contained no liver                         an individual who is a regular user of                warnings. NDAC recommended a liver
                                               pathology information. AST and ALT                      alcohol, in a prolonged fasting or in a               toxicity statement, separate from the
                                               levels were not reported in 108 cases (38               rapid weight loss program, the upper                  alcohol warning, be added to the label
                                               percent). Only 61 reports (25 percent)                  limit of a safe dose is unknown, but                  so that the potential for liver toxicity
                                               had information about viral hepatitis                   unlikely to not exceed 2 g of                         would not appear to be applicable only
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                                               testing and, of these, 29 reports were                  acetaminophen. No data were provided                  to consumers who drink alcohol. NDAC
                                               positive for hepatitis A, B, or C.                      to support these observations.                        noted that alcohol is not the only risk
                                                  5. There are flaws in the derivation of                 • Several organizations urged that                 factor for hepatotoxicity. It was also felt
                                               FDA’s theory that alcohol use,                          labeling be improved to provide clear                 to be important to warn consumers of
                                               underlying/history of liver disease, and                directions about the appropriate doses                the consequences of taking multiple
                                               potentially the use of hepatotoxic                      for use and frequency of administration,              products containing acetaminophen and
                                               concomitant medications, may increase                   especially for combination products                   that toxicity can be related to the total


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                                               77324                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               dose of acetaminophen taken during a                    potential toxicity, but noted that there is           C. Aspirin and Other NSAIDs
                                               given period of time. NDAC felt it                      a lack of information to support such                   On the second day of the meeting
                                               would be more prudent to describe                       labeling.                                             (September 20, 2002), NDAC considered
                                               these risks in a separate warning to                       One NDAC member mentioned that
                                                                                                                                                             safety issues related to the use of aspirin
                                               more fully inform consumers who do                      although some evidence appeared to
                                                                                                                                                             and other OTC NSAIDs. The primary
                                               not abuse alcohol.                                      show an association of increased
                                                                                                                                                             areas for discussion included the
                                                  NDAC did not propose exact                           acetaminophen toxicity for patients
                                                                                                                                                             potential for GI bleeding and renal
                                               language. It was believed that it was                   with pre-existing liver disease, this
                                                                                                                                                             toxicity from using these drugs. The
                                               important that the message not refer to                 finding is contrary to hepatologists’
                                               ‘‘overdose,’’ but rather to a statement                 experience with acetaminophen.                        prescription labeling for NSAIDs and
                                               such as ‘‘do not take more’’ or ‘‘do not                Generally, acetaminophen is considered                the professional labeling for aspirin
                                               exceed the recommended dose.’’ NDAC                     safe for use in patients with liver                   have warnings for GI bleeding and
                                               believed that the term ‘‘overdose’’                     disease, including people awaiting liver              possible renal toxicity. Aside from the
                                               would not be understood to be pertinent                 transplantation. Most hepatologists                   alcohol warning required on all OTC
                                               to consumers whose intent was to use                    recommend acetaminophen for such                      NSAID drug products, current OTC
                                               the product safely. One NDAC member                     patients, but at reduced doses, such as               labeling does not have warnings about
                                               stated the term ‘‘exceed’’ is not part of               2 g maximum in a 24-hour period.                      damage to specific organs.
                                               consumers’ common vocabulary and                        NDAC urged more studies, not only of                  1. Points for Discussion
                                               proposed that it would be more useful                   risk factors, but of a plan to reduce risk.
                                               to inform consumers of a specific                          • Consumer and healthcare provider                   FDA asked NDAC to consider the
                                               allowable total dose (e.g., not to take                 education. NDAC concluded that FDA                    relative risks for GI bleeding and renal
                                               more than a specified number of tablets                 and manufacturers have a joint                        toxicity associated with OTC doses of
                                               in a given period).                                     responsibility to reduce the occurrence               NSAIDs, including aspirin, and to
                                                  NDAC re-examined the currently                       of unintentional overdoses from                       consider the following issues:
                                               required alcohol warning for                            acetaminophen. NDAC considered it                       • How should the relative risk of GI
                                               acetaminophen, which states: ‘‘Alcohol                  essential that consumer and                           bleeding or renal toxicity be described
                                               Warning: If you consume 3 or more                       professional educational programs                     to consumers who use the maximum
                                               alcoholic drinks every day, ask your                    heighten awareness of the risk,                       recommended daily OTC dose?
                                               doctor whether you should take                          particularly to certain populations.                    • Are there subpopulations of
                                               acetaminophen or other pain relievers/                  NDAC believed consumers are                           consumers who are at a greater risk for
                                               fever reducers. Acetaminophen may                       unfamiliar with the term                              developing GI bleeding or renal toxicity
                                               cause liver damage.’’ NDAC inquired                     ‘‘acetaminophen’’ and are more likely to              with OTC doses?
                                               why ‘‘three drinks’’ were used in the                   know the brand names. NDAC stated                       • If additional warnings are
                                               alcohol warning. FDA responded that                     that an effort should be made to create               recommended, should such warnings
                                               the number is from recommendations of                   a broader educational campaign to                     inform consumers about the risk,
                                               the American Heart Association as to                    inform consumers that acetaminophen                   provide information on the at-risk
                                               what constitutes excessive alcohol use.                 is an analgesic, because most people are              populations, or provide expanded
                                               FDA stated that it recognized this may                  familiar with aspirin and not with                    information to all consumers about
                                               seem arbitrary and asked NDAC to                        acetaminophen. NDAC also suggested                    symptoms of toxicity?
                                               provide further recommendations.                        that the packaging, display, format, and                • Should the warnings that are
                                               NDAC questioned whether doctors are                     wording recommendations in OTC drug                   currently in professional labeling for
                                               well-informed with proper information                   product labeling should also be                       aspirin be conveyed to consumers as
                                               about the relationship between alcohol                  extended to all product advertisements,               part of the OTC labeling?
                                               and acetaminophen use and whether                       both in print and media, because                        • If yes, which warnings should be
                                               educational efforts should also include                 advertising is an educational tool for                conveyed and how should they appear
                                               educational efforts directed at health                  many consumers.                                       in OTC drug product labeling?
                                               care professionals and consumers.                          NDAC stated that many physicians                     • Are any additional studies needed
                                               NDAC was concerned about the lack of                    and pharmacists may not be aware of                   to evaluate subpopulations at risk for
                                               available data on which to base such                    the risks of unintentional overdose.                  serious adverse events, labeling
                                               advice, noting that there is a lack of                  NDAC added that, along with consumer                  revisions, and any other issues?
                                               information about how to determine the                  education, professional programs are                    • Should the labeling and packaging
                                               amount of alcohol that may be harmful                   important, because prescription                       of these products more prominently
                                               to any individual. NDAC noted that                      products containing acetaminophen are                 state that the product contains aspirin or
                                               reducing the risk of drug adverse events                widely used. Education of pharmacists                 the specific NSAID?
                                               is the goal, but believed that more data                would be needed to support the use of
                                                                                                                                                             2. Presentations and Submissions to
                                               are essential for them to make specific                 additional labeling information (stick-on
                                                                                                                                                             NDAC
                                               recommendations.                                        labels, etc.) attached to prescription
                                                  FDA asked NDAC to comment on                         containers. NDAC stated that auxiliary                GI bleeding
                                               whether the current maximum                             labeling is critical to conveying                       FDA staff described cases of GI
                                               allowable daily dose of acetaminophen                   information that the prescription                     bleeding (spontaneous reports from
                                               should be used by individuals                           product contains acetaminophen.                       AERS received by FDA between 1998
                                               consuming three or more drinks per                         • Pediatric dosage. NDAC also                      and 2001) in individuals who used OTC
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                                               day. One NDAC member agreed that                        expressed concern about the lack of                   NSAIDS (including aspirin) as an
                                               was prudent to lower the dose, however,                 standardized pediatric dosage                         analgesic and/or antipyretic (Ref. 8).
                                               the majority of NDAC members believed                   information, especially for infants under             The review was limited to cases that
                                               that more information is needed before                  2 years of age. FDA stated that a                     mentioned ‘‘OTC’’ in the narrative of the
                                               dose reductions could be implemented                    separate rulemaking on this issue was in              report. Any cases that appeared to
                                               for this population. NDAC stated that,                  progress and will be addressed in a                   involve prescription NSAID products
                                               intuitively, a lower dose would decrease                future Federal Register publication.                  were excluded. A total of 279 cases of


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77325

                                               GI bleeding were included: 82 for                       the incidence of complicated                          aspirin every day. The study showed
                                               aspirin and 197 for nonaspirin NSAIDs                   ulcerations (specifically, bleeding                   that there is an increased risk of upper
                                               (i.e., ibuprofen, ketoprofen, and                       ulcers) has increased in the past few                 GI bleeding in patients who combine
                                               naproxen). The mean age was 59 years                    years. This is likely due to increased                low dose aspirin and other NSAIDs
                                               (ranging from 1 to 99 years). There were                NSAID exposure, possibly from OTC                     compared to the incidence of GI
                                               138 (49.5 percent) males, 119 (42.7                     use. Gastric ulceration (15 percent                   bleeding events in the general
                                               percent) females, and 22 cases (7.9                     prevalence) associated with NSAIDs (at                population (RR 5.6; 95% confidence
                                               percent) in which gender was not                        recommended doses) is much more                       interval (CI) 4.4—7.0). The risk of GI
                                               reported.                                               common than duodenal ulceration (5                    bleeding among patients taking more
                                                  Cases that specified the location in                 percent prevalence). Clinically relevant              than one NSAID was approximately
                                               the GI tract of the bleed included:                     ulceration (i.e., ulcers that present with            double the risk among patients taking
                                               Stomach (63 cases), duodenum (35                        bleeding), has a prevalence of                        aspirin alone.
                                               cases), unspecified upper GI site (15                   approximately 2 percent.                                 • In an American College of
                                               cases), esophagus (13 cases), and                          • A history of prior bleeding,                     Gastroenterology Bleeding Registry (Ref.
                                               rectum/colon/small intestine (9 cases).                 anticoagulant use, corticosteroid use,                18), cases of GI bleeding were assessed
                                               For nonaspirin NSAIDs, the median                       and increasing age are factors that                   for use of aspirin or OTC NSAIDs and
                                               time to onset was 7 days. Time to onset                 increase the risk of bleeding associated              concomitant use of alcohol. These cases
                                               was defined as the time between each                    with NSAIDs (Refs. 10 through 13).                    were compared to data from a control
                                               person’s first use of the drug and the                     • The prevalence of upper GI                       cohort of cases with no GI bleeding. The
                                               time that bleeding occurred. For aspirin,               bleeding from aspirin use is different                results suggest an increased risk of
                                               time to onset was about 30 days. For                    than for nonaspirin NSAID use. A study                bleeding when alcohol is used while
                                               both aspirin and nonaspirin NSAIDs,                     evaluated the prevalence of aspirin and               taking an OTC NSAID (odds ratio 4.47;
                                               there was a wide range in time to onset.                nonaspirin NSAID use in 421 patients                  95 percent CI 2.73 -7.32) compared to
                                               FDA reviewed the cases for common                       evaluated for upper GI bleeding (Ref.                 the use of either alcohol or OTC NSAIDs
                                               risk factors for GI bleeding that are                   14). Patients were asked at the time of               alone (odds ratio for alcohol alone 2.07;
                                               recognized in the medical literature,                   hospital admission whether they were                  95 percent CI 1.48—2.88/ odds ratio for
                                               including previous GI bleed or history                  using prescription or OTC products and                NSAID alone 2.76; 95 percent CI 2.03—
                                               of an ulcer, social history (alcohol or                 whether they were using nonaspirin
                                                                                                                                                             3.74). Dr. Cryer noted that the results of
                                               tobacco use), concomitant use of other                  NSAIDs or aspirin. The results show
                                                                                                                                                             the study were confounded because 12
                                               drugs (NSAIDs, aspirin, anticoagulants,                 that 42 percent of GI bleeding was
                                                                                                                                                             percent of the subjects in the registry
                                               corticosteroids), use of doses higher                   associated with aspirin use. Fourteen
                                                                                                                                                             had gastric or esophageal varices
                                               than recommended, and advanced age                      percent of patients admitted to the
                                                                                                                                                             (enlarged veins). He suggested that there
                                               (65 years and older). The results                       hospital were using prescription
                                                                                                                                                             may be an increased risk particularly to
                                               included 195 (70 percent) cases with at                 NSAIDs and 9 percent were using OTC
                                                                                                                                                             patients with an extensive history of
                                               least one risk factor, 112 (40 percent)                 NSAIDs.
                                                                                                          • A recent study suggests that up to               alcohol use who are exposed to OTC
                                               cases with more than one risk factor,                                                                         NSAIDs.
                                                                                                       80 percent of people with GI bleeding
                                               and 81 (29 percent) cases with no risk
                                                                                                       are taking an NSAID, primarily low dose                  • Another report (Ref. 19) evaluated
                                               factors apparent in the report. The most                                                                      subjects who regularly or occasionally
                                                                                                       aspirin (Ref. 15). The relative risk (RR)
                                               commonly reported risk factors were:                                                                          used aspirin or ibuprofen and compared
                                                  • Concomitant use of another NSAID                   (i.e., the probability of an event in the
                                                                                                       active group divided by the probability               the RR of GI bleeding between those
                                               or aspirin (50 percent)                                                                                       who never used alcohol and those who
                                                  • Advanced age (40 percent)                          of the event in the control group) was
                                                                                                       2.4 for a low/medium NSAID dose and                   used alcohol. The results suggest a
                                                  • History of a previous GI bleed (18                                                                       modest increase in RR of upper GI
                                               percent)                                                4.9 for a high dose.
                                                  • Using NSAID doses above the                           • Another study compared the use of                bleeding in alcohol users; however, the
                                                                                                       OTC aspirin, ibuprofen, naproxen, and                 statistical analyses did not provide a
                                               recommended OTC dose (14 percent)
                                                  • Alcohol or tobacco use (5 percent).                acetaminophen between two case                        strong distinction between alcohol users
                                                  In the aspirin cases, only one person                groups, one group who experienced GI                  and non-users.
                                               was reported to have exceeded the OTC                   bleeding events and a control group of                   Dr. Marie Griffin of Vanderbilt
                                               recommended dose. Of the 279 aspirin                    cases who did not experience GI                       University discussed additional
                                               and nonaspirin cases, 212 people (76                    bleeding (Ref 16). The patients in the GI             information obtained from large
                                               percent) were hospitalized. Most                        bleeding group were more likely to be                 population studies regarding GI
                                               recovered; however, 13 (4.7 percent)                    taking aspirin or OTC NSAIDs prior to                 complications associated with the use of
                                               people died.                                            the GI bleeding event than were patients              NSAIDs (Ref. 20). She made the
                                                  FDA indicated that these reports                     in the control group. The extent of use               following points:
                                               suggest that serious GI bleeding events                 of acetaminophen was comparable                          • The risk of ulcer disease was shown
                                               can occur with NSAID and aspirin use                    between the two groups. This study                    to increase 10-fold in older people and
                                               at OTC dosage strengths, within the                     included people with chronic disease                  this risk is increased further by use of
                                               duration of use described in the OTC                    and chronic analgesic exposure,                       NSAIDs (Ref. 21). This ulcer
                                               labeling.                                               providing information about a subgroup                hospitalization study found the absolute
                                                  Dr. Byron Cryer, of the University of                of patients that may be different from                risks to increase from approximately 4
                                               Texas Southwestern Medical School,                      relatively healthy individuals exposed                hospitalizations per 1,000 person-years
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                                               provided an overview of the GI risks                    to OTC analgesics for acute, short-term,              in older non-users of NSAIDs to
                                               from NSAID use (Ref. 9). His review was                 or intermittent use.                                  approximately 16 hospitalizations per
                                               not limited to OTC dosing of NSAIDs                        • The risk of combining low dose                   1,000 person-years in older users of
                                               and extended to all NSAIDs. He made                     aspirin with nonaspirin NSAIDs was                    NSAIDs. In general, consumers taking
                                               the following points:                                   examined in a large national cohort                   NSAIDs for a year at moderate doses
                                                  • Despite the overall decrease in                    study in Denmark (Ref. 17) in which                   have about a 1 to 2 percent chance of
                                               prevalence of uncomplicated ulceration,                 27,000 people were given 100 to 150 mg                being hospitalized with a complication.


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                                               77326                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                                 • The risk of hospitalization for                     low risk. Results of prevention studies               sold), of fatalities associated with
                                               peptic ulcer disease (PUD), and risk of                 of secondary and acute myocardial                     acetaminophen overdose in the United
                                               GI complications, increases with                        infarction have shown that for people                 States significantly exceeds the
                                               increasing NSAID doses (Refs. 20, 22,                   whose 10-year risk of having a                        corresponding figures for aspirin
                                               and 23).                                                subsequent cardiovascular event is                    overdose.
                                                 • Data obtained from the Tennessee                    between 20 and 50 percent, the                           • One manufacturer stated that the
                                               Medicaid database indicate that the                     cardiovascular benefit of aspirin far                 occurrence of GI adverse events with
                                               greatest absolute risk for hospitalization              outweighs the risks. The relative and                 naproxen/naproxen sodium at single
                                               for PUD occurs in the first 30 days of                  absolute risks of aspirin are low.                    low dose (220 mg), at multiple doses (up
                                               NSAID use among patients older than                        • One consumer advocacy                            to 880 mg), and as needed OTC doses,
                                               65 years of age (Ref. 23). For older                    organization stated that GI bleeding                  are comparable to the occurrence
                                               patients, there were 26.3                               caused by NSAIDs (reference to                        associated with use of placebo (Ref. 5,
                                               hospitalizations for PUD per 1,000                      prescription or OTC products was not                  Tab H). Nausea, dyspepsia, and
                                               NSAID users per year within 30 days of                  specified) is now recognized as the most              vomiting are the most common GI
                                               starting NSAID therapy, 20.9                            common serious adverse drug reaction                  adverse events.
                                               hospitalizations between 31 and 180                     in the United States and accounts for as              Renal effects
                                               days of use, and 16.2 hospitalizations                  many as 16,000 deaths a year. The                        FDA staff presented information about
                                               for use longer than 180 days. In contrast,              organization requested that: (1) Product              the potential for OTC NSAIDs to cause
                                               there were 4.2 hospitalizations per 1,000               labeling contain a clear organ-specific               nephrotoxicity (Ref. 24) and made the
                                               NSAID non-users per year. Overall,                      warning about GI bleeding, (2)                        following points:
                                               people of all ages have a 1 to 2 percent                packaging include consumer education                     • NSAID-induced nephrotoxicity at
                                               chance of being hospitalized with a                     on GI bleeding, such as a leaflet inside              prescription doses is characterized by
                                               complication when using NSAIDs for                      the packaging listing specific symptoms               fluid and electrolyte disturbances
                                               over a year at moderate doses.                          and factors associated with increased                 leading to sodium retention, edema
                                                 • Surveys in the 1980s showed that                    risk, and (3) a separate warning, about               (accumulation of watery fluid in cells
                                               approximately 1 to 3 percent of people                  increased risk of GI bleeding associated              and tissues), and hyperkalemia (high
                                               65 and older take a prescription                        with alcohol use, be added and directed               concentration of potassium in the
                                               corticosteroid drug. The concomitant                    at consumers who drink some alcohol.                  blood). These drugs can also cause
                                               use of an OTC NSAID with a                                 Several drug manufacturers submitted               blood pressure to increase. The majority
                                               corticosteroid increases the risk of ulcer              additional information (Ref. 5):                      of healthy people who are exposed to
                                               complication 13- to 15-fold over NSAID                     • One manufacturer stated that the                 therapeutic doses of NSAIDs for a
                                               non-users. The ulcer hospitalization rate               safety profile for OTC ibuprofen,                     limited time tolerate these drugs
                                               in people using both drugs was about 5                  generated over 18 years of OTC use by                 without untoward renal effects. Some
                                               to 6 per 100 people per year.                           millions of consumers, indicates that                 subsets of the population are more
                                                 • In the 1980s, 1 to 2 percent of the                 the current labeling has been effective in            susceptible to potentially life-
                                               elderly population were co-prescribed                   informing consumers of the appropriate                threatening nephrotoxicity (e.g., acute
                                               warfarin (an anticoagulant drug) and                    use of the drug (Ref. 5, Tab E). The                  renal failure and serious fluid and
                                               NSAIDs. The risk of GI bleeding                         manufacturer stated that FDA has                      electrolyte disorders), including people
                                               increased by 12 fold in patients who                    received an average of 18 reports per                 who have volume depletion, underlying
                                               used both therapies compared to NSAID                   year of GI perforations, ulcers, or                   kidney disease, congestive heart failure,
                                               non-users. The risk of hospitalization                  hemorrhage associated with OTC use.                   or liver dysfunction with ascites
                                               for GI bleeding is approximately 3 per                     • One manufacturer stated that no                  (accumulation of fluid in the peritoneal
                                               100 per year in patients who use                        antidote is available for aspirin or                  cavity of the abdomen), and the elderly.
                                               warfarin and NSAIDs.                                    ibuprofen overdose (Ref. 5 Tab F). Acute              The use of NSAIDs in the last trimester
                                                 Several drug manufacturers and                        overdose and chronic aspirin toxicity                 of pregnancy has been associated with
                                               others provided additional comments                     are associated with significant                       significant neonatal nephrotoxicity.
                                               (Ref. 4):                                               morbidity (as high as 25 percent). If                    • Ideally, an assessment of the
                                                 • One drug manufacturer of ibuprofen                  acetaminophen was restricted, aspirin                 nephrotoxic risk associated with OTC
                                               OTC drug products stated that the OTC                   and other NSAID use would increase.                   NSAIDs should rely on data derived
                                               ibuprofen daily regimen is 1,200 mg/day                 Available data suggest that more people               from prospective, randomized, placebo-
                                               versus 2,400 to 3,200 mg a day for                      would die from aspirin and other                      controlled and adequately powered
                                               prescription use. Unlike                                NSAID-related GI bleeding. The net                    studies in healthy, as well as at-risk,
                                               acetaminophen, the OTC directions                       public health impact of changing                      populations. However, such data are not
                                               clearly state to take one 200-mg tablet                 labeling for OTC IAAA drug products                   available. In 1995, the National Kidney
                                               and, only if necessary, a second tablet                 should be taken into consideration in                 Foundation (NKF) convened a group of
                                               may be taken. OTC use of NSAIDs is                      the formulation of any regulatory policy.             investigators and clinicians to consider
                                               limited to a maximum of 10 days,                           • One manufacturer stated that the                 and develop recommendations on the
                                               whereas prescription use is chronic.                    risk patterns associated with use of                  issue of analgesic-related kidney
                                                 • One drug manufacturer stated that                   acetaminophen and aspirin are distinct                disease. The database used to make their
                                               each analgesic ingredient requires                      from one another and support different                recommendations was comprised of 556
                                               appropriate labeling for its pattern of                 product labeling for the various                      articles published in the medical
                                               use and that it is inappropriate to label               ingredients in OTC IAAA drug products                 literature on aspirin, acetaminophen,
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                                               OTC products with risks associated with                 (Ref. 5, Tab G). There are no data to                 aspirin-acetaminophen combinations,
                                               chronic, long-term prescription dosing.                 support the view that a balanced                      and NSAID-related nephrotoxicity. The
                                               The prescription and OTC uses of                        warning for acetaminophen will cause a                NKF recommended ‘‘[t]here should be
                                               NSAIDs are distinct and these two dose                  significant number of patients to switch              an explicit label warning people taking
                                               levels have different risk-benefit                      to another OTC analgesic. Available                   over-the-counter NSAIDs of the
                                               profiles. The OTC use is short-term for                 data indicate that both the absolute                  potential renal risks of consuming the
                                               pain relief and fever reduction, with a                 number, and the rate (per billion tablets             drugs.’’


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77327

                                                  • FDA staff identified all cases in the              OTC dosages and/or an OTC NSAID                       and nine died. Renal failure occurred
                                               AERS database reporting acute renal                     product had a role in the adverse                     within less than 7 days of exposure to
                                               failure, chronic renal failure, and renal               reaction. People with pre-existing                    the drug. Fourteen ibuprofen cases were
                                               failure in association with the use of                  conditions were not included. Table 9                 within the pediatric age group. For
                                               OTC doses of NSAIDs. The time period                    shows the number of cases of renal                    naproxen sodium, 25 people were
                                               reviewed was from the OTC approval                      failure reported, including 94 cases for              hospitalized, 4 required dialysis, and 3
                                               date for ibuprofen (1984), naproxen                     ibuprofen, 26 cases for naproxen                      died. The single ketoprofen case was
                                               sodium (1994), and ketoprofen (1995)                    sodium, and 1 case for ketoprofen. Fifty-             hospitalized.
                                               through August 10, 1999. FDA’s review                   six people who used ibuprofen required
                                               included cases that specified that either               hospitalization; nine needed dialysis;

                                                                           TABLE 9.—FDA AERS CASES OF RENAL FAILURE AT OTC DOSES OF NSAIDS
                                                                                                                Ibuprofen                        Naproxen Sodium                  Ketoprofen

                                                 Reporting Period                                                            15 years                             5 years                      4 years

                                                 Renal Failure Cases—Total                                                          94                                 26                           1

                                                 Renal Failure Cases—Adult                                                          80                                 26                           1

                                                 Renal Failure Cases—Pediatric                                                      14                                   0                          0



                                                  Next, Dr. Griffin discussed renal                      Several drug manufacturers submitted                warning. One NDAC member suggested
                                               complications from the use of NSAIDs                    additional information suggesting that                the heading ‘‘bleeding alert’’ because
                                               obtained from large population studies                  (Ref. 5):                                             aspirin and the other NSAIDs can cause
                                               (Ref. 20). A study of patients 65 years                   • The number of renal side effects                  more than stomach bleeding, and it is
                                               of age and older in the Tennessee                       that have been reported with OTC                      very important to stop using an OTC
                                               Medicaid database (Ref. 23) included                    ibuprofen are minimal (less than two                  IAAA active ingredient when signs of
                                               the following information:                              cases of renal failure per year),                     bleeding are present (e.g., vomiting
                                                                                                       confirming that the drug is well-                     blood or bloody or black stools). Most
                                                  • Eighteen percent of the patients
                                                                                                       tolerated.                                            NDAC members felt that stomach
                                               presenting with acute renal failure used                  • The renal safety profile of
                                               NSAIDs at either prescription or OTC                                                                          bleeding was the major safety problem
                                                                                                       naproxen/naproxen sodium is                           and should be the focus of the warning
                                               doses. A RR for acute renal failure in                  consistent with other currently
                                               NSAID users was calculated to be 1.58                                                                         statement.
                                                                                                       marketed NSAIDs with which it has                        NDAC found that low dose aspirin,
                                               compared to NSAID non-users.                            been compared. Even at prescription                   combined with another NSAID, will
                                                  • The RR for acute renal failure with                doses, reports of adverse events                      increase the risk for GI bleeding two to
                                               ibuprofen was dose related. The RR of                   involving the kidney have been rare.                  four times more than use of an NSAID
                                               acute renal failure associated with use
                                                                                                       3. NDAC Deliberations and                             alone. From the data reviewed, enteric-
                                               of daily doses of less than 1,200 mg was
                                                                                                       Recommendations Concerning Aspirin                    coated or buffered aspirin preparations
                                               approximately 1 compared to use of no
                                                                                                       and Other NSAIDs                                      do not change the risk associated with
                                               ibuprofen. Daily doses of 1,200 to 2,400
                                                                                                          • GI bleeding. NDAC members agreed                 use of multiple NSAID products. NDAC
                                               mg (above the OTC range of 1,200 mg
                                                                                                       that NSAIDs increase the risk for GI                  recommended that the labeling for
                                               per day or less) increased the RR of
                                                                                                       adverse events. The risk appears to be                aspirin and other NSAIDs include a
                                               renal failure to 1.89.
                                                                                                       related to dose. Aspirin, even at lower               stomach bleeding warning advising
                                                  • The greatest risk for renal failure                                                                      consumers of the risks of taking more
                                                                                                       doses, has some GI risks. However, the
                                               was within the first 30 days of therapy                                                                       than directed or using more than one
                                                                                                       benefits from use far exceed any risks.
                                               with an NSAID. The RR was 2.83.                                                                               NSAID. In addition, NDAC concluded
                                                                                                       NDAC stated that low dose aspirin
                                                  Several drug manufacturers and                       should be available OTC for the elderly               that the warning should advise
                                               others provided additional comments                     for cardiovascular prophylaxis as                     consumers that the risk is greater for
                                               (Ref. 4). One drug manufacturer stated                  described in the professional labeling.               individuals who are over 65 years of
                                               that the incidence of renal failure and                 NDAC believed that the absolute risk of               age, have a history of ulcers, stomach,
                                               other serious renal events are rare with                GI bleeding from use of low dose aspirin              or bleeding problems, or are taking
                                               use of either prescription or OTC                       is probably comparable to the risk from               steroids or anticoagulants (blood
                                               ibuprofen. One drug manufacturer                        using aspirin at analgesic doses.                     thinners).
                                               claimed that there was an average of                    Therefore, NDAC recommended that the                     A majority of NDAC members
                                               approximately five reports of renal                     information on risk provided in OTC                   believed that there were insufficient
                                               failure per year from FDA’s safety                      aspirin labeling to consumers need not                data and a lack of a scientific rationale
                                               surveillance data. The manufacturers                    be categorized by dose.                               to support a warning about using
                                               also suggested that serious renal events                   NDAC agreed that the data support a                alcohol while taking NSAIDs.
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                                               are almost always reversible, even in the               separate and distinct stomach bleeding                Recognizing that the data are mixed and
                                               elderly or chronically ill. It was stated               warning and suggested that the heading                not conclusive, the members believed
                                               that serious renal events following                     ‘‘stomach bleeding warning’’ be used.                 that a majority of the trials reviewed
                                               NSAID therapy almost always occur in                    NDAC recommended that this heading                    failed to show a direct and convincing
                                               patients with pre-existing renal                        be in bold type and that the warning be               association with alcohol. NDAC urged
                                               dysfunction, congestive heart failure, or               included as one of the first warnings in              FDA to remove the existing alcohol
                                               compromised hepatic function.                           labeling along with the Reye’s syndrome               warning from labeling and encouraged


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                                               77328                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               FDA to examine future cases of GI                       IV. FDA’s Review of Additional Data                   NDAC meeting, FDA conducted a
                                               bleeding in individuals who consume                     and Information                                       literature review (1966 to January 2003)
                                               alcohol and are alcohol abusers to                                                                            and determined that the following
                                                                                                       A. Pre-existing Liver Disease as a Risk
                                               explore the impact of concomitant use                                                                         factors may place patients with pre-
                                                                                                       Factor for Acetaminophen
                                               of NSAIDs.                                                                                                    existing liver disease at a greater risk for
                                                                                                       Hepatotoxicity
                                                                                                                                                             acetaminophen toxicity (Ref. 26).
                                                  • Renal effects. NDAC considered                        Following publication of the OTC                      • Depletion of hepatic GSH has been
                                               particular groups at risk for short-term                IAAA TFM in 1988, FDA received                        found in both alcoholic and
                                               adverse renal consequences from NSAID                   comments urging adoption of a warning                 nonalcoholic liver diseases, suggesting
                                               use. While NDAC agreed that small                       to advise consumers with pre-existing                 that the diseased liver may have less
                                               increases in blood pressure of limited                  liver disease against using                           capacity to inactivate the toxic
                                               duration (e.g., several days) in                        acetaminophen, unless directed by a                   metabolite of acetaminophen. (Refs. 27
                                               normotensive or hypertensive                            doctor. The comments cited reports in                 through 34)
                                               individuals is not a significant risk, the              the medical literature concerning                        • The hepatic cytochrome P450
                                               labeling for NSAIDs should warn about                   toxicity in persons with liver disease.               enzyme, P450–2E1, metabolizes
                                               the potential association of long-term                  Other comments asserted that there is                 acetaminophen to the toxic metabolite
                                               use and renal failure in individuals who                no evidence to warrant a warning. At                  that causes hepatotoxicity. Expression
                                               have high blood pressure, heart or                      that time, FDA believed the evidence                  of hepatic P450–2E1 tends to increase in
                                               kidney disease, use diuretics, or are over              was insufficient to propose a warning.                stable chronic liver diseases.
                                               65 years of age. NDAC agreed with the                   NDAC briefly discussed this issue in                     • Studies have shown that the
                                               OTC labeling proposed for ibuprofen in                  September 2002, but concluded that                    clearance of acetaminophen from the
                                               the Federal Register of August 21, 2002,                there were not sufficient data to make                body is impaired in people with chronic
                                               including the warning to ask a doctor                   specific recommendations.                             liver disease (Refs. 35, 36, and 37). The
                                               before use in the presence of high blood                   FDA has reconsidered its previous                  disease status of the liver alters drug
                                               pressure, heart or kidney disease, if also              position on this issue and now believes               metabolism and drug metabolites made
                                               using a diuretic, or if over 65 years of                that the current evidence supports a                  by each metabolic pathway (Refs. 38
                                               age.                                                    warning. At the NDAC meeting, FDA                     and 39).
                                                                                                       reported information derived from                        • In chronic liver disease, hepatic
                                                  Labeling. NDAC members agreed that                   mortality data of acetaminophen                       glucuronide and sulfate conjugation are
                                               labeling continues to be a major factor                 overdose (intentional and                             decreased (Refs. 40 through 43).
                                               in promoting the safe and effective use                 unintentional). Among patients with                      • Significant impairment of total
                                               of OTC NSAID products. NDAC                             chronic alcoholic or other chronic liver              hepatic P450 expression is found only
                                               expressed concern that consumers do                     disease, death associated with                        in people with severe liver disease
                                               not read labels adequately and are often                unintentional acetaminophen overdose                  (hepatitis with liver failure and
                                               unaware of the names of the medicines                   was reported far more frequently than in              decompensated cirrhosis) (Ref. 38).
                                               that they are taking. This lack of                      association with intentional overdose                 Recent studies indicate that different
                                               awareness is especially problematic for                 (see table 4 of this document). In the                types (viral, chemical, or immunological
                                               people who are also taking prescription                 series of 282 AERS cases of hepatoxicity              factors) and/or states (acute, chronic, or
                                               medicines concomitantly with OTC                        associated with acetaminophen use                     severe) of liver disease selectively
                                               drug products. NDAC expressed                           presented at the meeting, 70 cases were               influence expression of different P450
                                               concern about the ability to                            reported as having underlying liver                   isozymes.
                                               communicate meaningful information in                   disease.                                                 • Chronic alcohol use significantly
                                               the confines of a small package label,                     Metabolic activation and deactivation              induces hepatic P450–2E1 and increases
                                               especially to the elderly. NDAC                         are involved in acetaminophen                         this enzyme’s ability to metabolize
                                               suggested that patient information be                   elimination (Ref. 25). At a therapeutic               acetaminophen to NAPQI (Ref. 44). In
                                               included in a package insert to provide                 dose, the majority (greater than 90                   other types of human liver disease,
                                               expanded information beyond what                        percent) of acetaminophen combines                    changes in expression and activity of
                                               could be presented clearly on a small                   with glucuronic acid (the major                       P450–2E1, as well as other P450
                                               label.                                                  metabolic pathway for adults) and                     isozymes (1A2 and 3A4) involved in
                                                                                                       sulfuric acid (the major metabolic                    acetaminophen metabolism, are variable
                                                  NDAC strongly recommend that the                     pathway for children). There is also a                (Refs. 38, 45, 46, and 47). Both human
                                               term ‘‘NSAID’’ be used throughout OTC                   second, minor metabolic pathway in                    and animal studies show that hepatic
                                               product labeling. The term NSAID is                     which a small portion of acetaminophen                P450–2E1 expression is significantly
                                               becoming more widely recognized and                     undergoes cytochrome P450 phase I                     increased in a nonalcoholic fatty liver
                                               is often found in drug information                      metabolism to the toxic acetaminophen                 (Refs. 48 and 49).
                                               leaflets. NDAC suggested that meaning                   metabolite, N-acetyl-p-                                  Few clinical trials directly assess the
                                               of the NSAID acronym could be spelled                   benzoquinoneimine (NAPQI). This toxic                 hepatotoxicity of acetaminophen in
                                               out somewhere on the label.                             metabolite is normally inactivated                    people with nonalcoholic liver disease.
                                               Additionally, NDAC recommended that                     through combination with hepatic                      One double-blind, placebo controlled,
                                               this term should be included on the                     glutathione (GSH). Any factors that can               crossover study was conducted in 20
                                               front panel or PDP, advising consumers                  change GSH availability (by decreasing                people with stable chronic liver disease
                                               that the product contains an NSAID,                     synthesis and/or increasing utilization               (including Laennec’s cirrhosis, alcoholic
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                                               especially if the product is a                          or interfering with the conjugation                   liver cirrhosis, primary biliary cirrhosis,
                                               combination containing an NSAID.                        enzyme) could potentially influence the               or chronic hepatitis) (Ref. 50). The
                                               Finally, NDAC members agreed that                       hepatotoxicity of acetaminophen. Any                  subjects received 1 g of acetaminophen
                                               there is a need for additional label                    factors that disturb the balance between              or placebo every 4 hours (a total of 4 g/
                                               comprehension studies to identify ways                  these two metabolic pathways may                      day) for 13 days. The author stated that
                                               to improve communication with                           affect the amount of acetaminophen                    there were no significant changes in
                                               consumers.                                              metabolized by each pathway. After the                laboratory tests or clinical status in the


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77329

                                               acetaminophen and placebo treatments.                      • 48% were designated as                           (Ref. 54). NSAID use is so widespread
                                               The author concluded that underlying                    unintentional injury, 44% were                        that NSAID-induced gastropathy has
                                               liver disease does not increase patient                 designated as an intentional injury and               been identified by some as one of the
                                               sensitivity to the hepatotoxic effects of               8% could not be classified to either                  most prevalent, serious drug toxicities
                                               acetaminophen at a therapeutic dose.                    group;                                                in the United States (Ref. 55). NSAID-
                                               Because of the small sample size and                       • 147 (53%) used an OTC product,                   associated serious GI complications are
                                               crossover study design, FDA believes                    including 6 of 147 who used more than                 estimated to result in over 200,000
                                               this study is inadequate to make any                    one OTC product at the same time and                  hospitalizations per year in the United
                                               conclusions regarding the risk for                      41 of 147 who also used a prescription                States. Although these adverse event
                                               acetaminophen hepatotoxicity in                         combination product;                                  rates are for prescription and OTC
                                               patients with chronic liver disease.                       • 120 (44%) reported use of a                      NSAID formulations combined, there is
                                                  In summary, the single prospective                   narcotic/acetaminophen combination;                   a significant prevalence of OTC NSAID
                                               clinical study found by FDA in the                         • 55% had a history of alcohol use                 use among people presenting to
                                               literature that evaluated the                           and 35% had a history of alcohol abuse;               hospitals with upper GI bleeding (Ref.
                                               susceptibility of the diseased liver to                    • 108 (39%) also used a                            56). The rate of consumption of OTC
                                               acetaminophen toxicity was not                          antidepressant;                                       NSAIDs by consumers is estimated to be
                                               definitive. Analyses of an                                 • 65% survived without transplant;                 as much as seven times that of
                                               acetaminophen overdose database and a                   and                                                   prescribed NSAIDs (Ref. 54).
                                               review of the AERS case reports suggest,                   • 22% used more than one                              • The American College of
                                               however, that people with a history of                  acetaminophen product.                                Gastroenterology guideline for treatment
                                               liver disease may have increased                           The authors also compared                          and prevention of NSAID-induced
                                               susceptibility to acetaminophen-                        characteristics between those classified              ulcers indicates an increased risk of
                                               induced hepatotoxicity. In addition, the                as unintentional versus intentional liver             NSAID-associated GI complications for
                                               depletion of hepatic GSH has been                       injury. Females predominate in both                   people greater than 60 years of age (Ref.
                                               found in both alcoholic and                             groups. The clinical outcomes are                     56). A United Kingdom (UK)
                                               nonalcoholic liver diseases, suggesting                 similar for both groups. Narcotic/                    population-based, retrospective case-
                                               that the diseased liver may have less                   acetaminophen use was more prevalent                  control study evaluated the risk of
                                               capacity to inactivate the toxic                        in the unintentional injury group (63%                various NSAIDs (Ref. 10). The study
                                               metabolite of acetaminophen.                            vs. 18%). The unintentional injury                    reported a RR of 3.7 for upper GI
                                               Expression of hepatic P450–2E1, a major                 group had a greater percentage with                   bleeding (UGIB) and GI perforation in
                                               enzyme for metabolic activation of                      stage 3-4 hepatic coma score at                       people under 60 years old exposed to
                                               acetaminophen, tends to be increased in                 admission and at peak during the                      NSAIDs, 13.2 in people 60 years and
                                               stable chronic liver diseases,                          hospitalization. FDA believes that these              older exposed to NSAIDs, and 2.8 in
                                               particularly in nonalcoholic fatty liver                data support the previous NDAC                        people 60 years and older not exposed
                                               disease. FDA believes that these data                   conclusion that acetaminophen                         to NSAIDs.
                                                                                                       hepatotoxicity is an important public                    • FDA analyzed a series of studies
                                               collectively establish that it is necessary
                                                                                                       health consideration and that additional              that used the Medicaid population in
                                               to alert patients with chronic liver
                                                                                                       labeling is necessary for it to continue              Tennessee (Refs. 12, 13, 56, 57, and 58).
                                               disease that they may be at risk for
                                                                                                       to be generally recognized as safe and                These case-controlled retrospective
                                               developing acetaminophen
                                                                                                       effective.                                            studies were based on hospitalizations
                                               hepatotoxicity, as an important factor in
                                                                                                                                                             for GI bleeds. The study population
                                               the safe and effective use of                           C. Aspirin and Other NSAIDs                           totaled 103,954 individuals, about 15
                                               acetaminophen products.
                                                                                                       1. GI Bleeding                                        percent of Tennessee’s elderly
                                               B. Updated Literature About                                                                                   population, with 209,066 person-years
                                               Acetaminophen Hepatoxicity                                Following the NDAC meeting, FDA                     of followup. There were 1,371
                                                                                                       reviewed additional data and                          hospitalizations for PUD. These studies
                                                 The Acute Liver Study Group recently                  information related to the use of OTC                 found increased risk of GI bleeds in
                                               published an update of the prospective                  NSAIDs and GI bleeding.                               people who were:
                                               data in patients diagnosed with ALF at                    • One individual asserted in a citizen                 • Over 65 years old (RR of 4.7),
                                               22 tertiary care centers. Over a 6-year                 petition that incomplete information                     • Taking an increased NSAID dose
                                               period from January 1, 1998, to                         about aspirin reaches consumers and                        (RR of 2.8 for the lowest dose vs. RR
                                               December 31, 2003, 662 patients                         increases the danger that aspirin will be                  of 8 for the highest dose category),
                                               fulfilled standard criteria for ALF. Of                 misused with serious consequences                          or
                                               these cases, 275 were attributed to                     (Ref. 52). The citizen petition suggested                • Taking concomitant corticosteroid
                                               acetaminophen hepatotoxicity. The                       that additional labeling for aspirin                       (RR of 4.4) or anti-coagulant (RR
                                               criteria for attribution to acetaminophen               should be implemented without delay                        12.7) drug products.
                                               included one or more of the following:                  to state: ‘‘CAUTION: This product can                    In addition, the risk of GI bleeds
                                               (1) A history of potentially toxic                      cause severe hemorrhaging and should                  among people taking NSAIDs was
                                               acetaminophen ingestion (> 4 g/day)                     not be taken for more than five days                  greatest within the first 30 days of use
                                               within 7 days of presentation; (2)                      except under the supervision of a                     (RR of 7.2).
                                               detection of any level of acetaminophen                 physician. When used for fever, if                       • A multicenter, case-control study of
                                               in the serum; or (3) a serum alanine                    symptoms persist more than three days,                550 people with UGIB admitted to a
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                                               aminotransferase (ALT) > 1,000 IU/L                     consult a physician.’’                                hospital with bloody stools or vomiting
                                               with a history of acetaminophen                           • NSAIDs are being used by an                       blood and 1,202 controls identified from
                                               ingestion, irrespective of acetaminophen                estimated 17 million Americans on a                   census lists, compared risks of major GI
                                               level (Ref. 51).                                        daily basis (Ref. 53). The estimated rate             bleeding for plain, coated, and buffered
                                                 Of the 275 cases attributed to                        of serious adverse events is about 1                  formulations of low-dose aspirin (Ref.
                                               acetaminophen, the following                            percent for clinically significant GI                 59). Each of these types of low-dose
                                               observations were made:                                 bleeding in the first 3 months of use                 aspirin formulations (less than 325 mg


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                                               77330                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               per day) had about a 2.5 to 3 times                     existing renal problems were prescribed               interstitial nephritis, which the authors
                                               increased risk of major UGIB.                           ibuprofen for the treatment of fever due              attributed to beta-lactam antibiotic use.
                                                  • A double-blind, randomized,                        to acute illness. Both had a recovery of                 These case reports demonstrate the
                                               placebo-controlled, ulcer prevention                    renal function on withdrawal of the                   variety of situations in which ibuprofen-
                                               study in 8,843 people with rheumatoid                   drug. The third child (a 7.5-year-old                 associated renal toxicity can occur. In
                                               arthritis identified several risk factors               girl) developed progressive chronic                   many of the cases, the children were
                                               for upper GI complications from NSAID                   renal failure. She had underlying hyper               already at risk for renal adverse effects
                                               use: (1) Age 75 years or older (odds ratio              Ig-E syndrome and was treated with a                  because of underlying disease states,
                                               2.48), (2) prior peptic ulcer (odds ratio               single dose of ibuprofen 5 mg /kg for                 concomitant medications, or
                                               2.29), (3) prior GI bleeding (odds ratio                fever due to severe pulmonary infection.              dehydration. Children with underlying
                                               2.56), and (4) history of cardiovascular                Her illness was also complicated by                   illnesses or those dehydrated are at
                                               disease (odds ratio 1.84) (Ref. 60).                    moderate dehydration. Her renal biopsy                greatest risk for this injury. FDA
                                                  • A case control study of 1,122                      showed evidence of kidney damage                      currently requires all OTC pediatric
                                               subjects admitted consecutively for                     consistent with loss of blood                         products containing ibuprofen marketed
                                               UGIB to four hospitals in Spain and                     circulation.                                          under new drug applications to include
                                               2,231 controls from the same geographic                    • Ibuprofen-induced acute renal                    warnings for children ages 2 to 11 years
                                               area, showed that a prior history of                    failure was reported in a 9-month-old                 to ask a doctor before use if the child
                                               UGIB is a risk factor (odds ratio 3.7) for              girl (Ref. 67). A family practitioner                 has ‘‘not been drinking fluids’’ or has
                                               UGIB in people who used NSAIDs (Ref.                    treated the infant for diarrhea, vomiting,            ‘‘lost a lot of fluid due to continued
                                               61).                                                    and fever. She was given oral                         vomiting or diarrhea.’’
                                                  In summary, results of several large-                rehydration therapy and acetaminophen                    b. Alcohol use. Binge drinking of
                                               scale clinical studies, conducted in the                                                                      alcohol reduces the production of
                                                                                                       and was sent home. Symptoms persisted
                                               United States and worldwide, have                                                                             antidiuretic hormone causing increased
                                                                                                       for 48 hours and the acetaminophen was
                                               established that use of OTC NSAIDs is                                                                         urine production. Two cases of
                                                                                                       changed to ibuprofen 50 mg (5 mg/kg/
                                               an important risk factor for serious GI                                                                       reversible acute deterioration in renal
                                                                                                       dose) three times a day. Seven doses of
                                               adverse events, especially bleeding. The                                                                      function following binge drinking of
                                                                                                       ibuprofen were given over a 40-hour
                                               risk is higher for people age 60 or older,                                                                    beer with use of NSAIDs have been
                                                                                                       period, but the child’s clinical state
                                               who have a history of stomach ulcers or                                                                       reported in adults (Ref. 69):
                                                                                                       deteriorated. She was admitted to an                     • The authors reported a case of a 22-
                                               bleeding problems, or who use                           emergency facility 18 hours after the last
                                               corticosteroids or anticoagulants.                                                                            year old male admitted to the hospital
                                                                                                       dose with a creatinine concentration of               with low back pain and worsening renal
                                               2. Renal Effects                                        2.1 mg/deciliter (dL). For the first 12               function. Four days prior to admission,
                                                  NSAIDs decrease renal prostaglandin                  hours after admission, the infant’s                   he had consumed an unknown amount
                                               production, which may result in acute                   kidneys failed to secrete urine in spite              of beer; 2 days later as the pain
                                               reduction in renal blood flow and                       of receiving adequate hydration and an                intensified he had taken six doses of
                                               glomerular filtration, leading to fluid                 intravenous diuretic (furosemide). The                400-mg ibuprofen with no relief. Upon
                                               retention, edema, and elevation of                      creatinine concentration increased to                 admission, his serum creatinine was 3.1
                                               serum creatinine (Ref. 62). Marked                      2.4 mg/dL. Renal function slowly                      mg/dL. Biopsy of the kidney was
                                               reduction in renal blood flow may result                recovered; 4 days after admission her                 consistent with the diagnosis of acute
                                               in renal failure.                                       creatinine was 0.9 mg/dL and 3 weeks                  kidney failure. The subject’s serum
                                                  NSAID use may also result in higher                  later was 0.5 mg/dL. Clinical diagnosis               creatinine increased to a peak of 6.5 mg/
                                               than normal levels of potassium in the                  was kidney damage secondary to                        dL on the fourth day and decreased to
                                               bloodstream. This occurs most                           ibuprofen use in a dehydrated child.                  1.4 mg/dL 6 days later.
                                               commonly in people with diabetes                           • Primack, et al. reported acute renal                • In a second case, a 20-year old male
                                               mellitus or mild to moderate renal                      failure with use of ibuprofen in an 11-               was admitted because of flank and back
                                               insufficiency as well as in people taking               year-old boy (Ref. 68). The child was                 pain of 24 hours’ duration. Four days
                                               beta-blocker, angiotensin-converting                    diagnosed with possible sinusitis and                 before admission, the subject drank 8 to
                                               enzyme inhibitor, or potassium-sparing                  given an antibiotic; on the third day                 10 bottles of beer (355 mL per bottle).
                                               diuretic drugs.                                         symptoms worsened with associated                     On the evening of admission, he had
                                                  By inhibiting the production of                      headaches, fatigue and anorexia, and his              taken 6 to 8 tablets of 325-mg aspirin for
                                               vasodilatory prostaglandins, NSAIDs                     serum creatinine was 0.7 mg/dL. The                   pain relief. The laboratory data showed
                                               may decrease renal blood flow and the                   antibiotic was continued and ibuprofen                a 2.0 mg/dL serum creatinine level.
                                               rate of glomerular filtration in subjects               200 mg was added, alternating with                    Following intravenous fluid
                                               with congestive heart failure, liver                    acetaminophen every 4 hours for fever.                administration, the subject urinated
                                               failure with ascites, chronic renal                     He received a total of 24 200-mg                      frequently for over 16 hours. Followup
                                               disease, or those who are hypovolemic                   ibuprofen tablets during the 12 days                  serum creatinine 1 week later was 1.2
                                               (abnormal volume decrease of                            prior to hospitalization. The fever                   mg/dL. The authors concluded that
                                               circulating fluid (plasma) in the body)                 persisted with improvement in the other               dehydration is a frequent consequence
                                               (Refs. 63, 64, and 65).                                 symptoms. The child became                            of heavy alcohol ingestion due to water
                                                  a. Pediatric population. The medical                 progressively weaker and began                        diuresis. The volume contraction may
                                               literature includes sporadic reports of                 vomiting. Approximately 2 weeks after                 be further aggravated by nausea and
                                               acute renal failure in pediatric subjects               his illness began, the child was                      vomiting.
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                                               taking ibuprofen within the OTC dose                    admitted with a serum creatinine of 7.6                  In the proposed rule to amend the
                                               range, including the following cases:                   milliequivalent/L. After 3 days of                    TFM for OTC IAAA drug products to
                                                  • One article describes three cases in               symptomatic treatment, his serum                      include ibuprofen, FDA included the
                                               children 5-, 6.5-, and 7.5-years-old in                 creatinine was 4.1 mg/dL and 1 week                   results of the agency’s evaluation of the
                                               which ibuprofen treatment led to                        later his serum creatinine was 2.2 mg/                adverse renal effects of OTC doses of
                                               varying degrees of renal failure (Ref. 66).             dL. Findings of renal biopsy on the third             ibuprofen (67 FR 54139 at 54144). Based
                                               Two subjects with dehydration and pre-                  hospital day were consistent with acute               on its evaluation of the data, FDA


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                           77331

                                               concluded that OTC doses of ibuprofen                     • Propose revised OTC labeling for                     FDA also tentatively concludes that a
                                               can exert a variety of adverse renal                    these products                                        new warning is needed to advise
                                               effects, particularly in those who are                    • Continue a consumer and health                    consumers who have liver disease to
                                               dependent on adequate prostaglandin                     provider educational campaign                         consult a doctor before using OTC drug
                                               levels to maintain renal hemodynamic                      • Continue to monitor AERS in                       products that contain acetaminophen.
                                               perfusion (i.e., congestive heart failure,              various databases                                     FDA notes that many of the case reports
                                               liver failure with ascites, etc.). It was                                                                     in the databases involved people who
                                                                                                         • Examine available data to
                                               further noted that although the sporadic                                                                      had pre-existing liver disease (the rate of
                                                                                                       determine whether other measures may
                                               nature of idiosyncratic drug-induced                                                                          the number of cases in the databases
                                                                                                       be needed in the future to try to
                                               ibuprofen nephrotoxicity makes it                                                                             exceeds the rate of underlying liver
                                                                                                       decrease morbidity associated with OTC
                                               impossible to predict which group of                                                                          disease in the general population). This
                                                                                                       acetaminophen and NSAIDs.
                                               individuals is at risk for developing this                                                                    observation may also be due to a
                                               event, this is not the case with                          In addition to the changes to the                   difference in the use of acetaminophen
                                               individuals who experience                              IAAA TFM proposed in this document,                   by people with chronic liver disease or
                                               prostaglandin-dependent hemodynamic                     FDA encourages manufacturers of these                 that they are at greater risk to develop
                                               changes. The latter, if recognized, is                  products to undertake education                       liver failure in general. As described in
                                               reversible upon discontinuation of the                  initiatives regarding safe use of OTC                 section IV.A of this document, people
                                               drug (67 FR 54139 at 54145).                            products containing acetaminophen and                 with chronic liver disease can have
                                                                                                       NSAIDs. FDA plans to increase its                     changes in the liver enzymes
                                               V. FDA’s Tentative Conclusions                          monitoring of AERS in various                         responsible for the metabolism of
                                                  FDA has carefully considered NDAC’s                  databases to see how this new proposed                acetaminophen. It is not clear whether
                                               recommendations and other available                     labeling, if implemented, is working to               these changes increase the risk in these
                                               data and information and determined                     reduce injuries resulting from OTC                    individuals. It was noted at NDAC that
                                               that labeling revisions are necessary for               acetaminophen and NSAID drug                          some physicians who treat patients with
                                               OTC IAAA drug products to advise                        products and to determine whether                     chronic liver disease recommend lower
                                               consumers of potential health risks and                 further measures need to be proposed.                 total daily doses. FDA believes this
                                               to recommend, under certain                                                                                   additional warning will alert patients
                                                                                                       A. Acetaminophen
                                               circumstances, that they consult a                                                                            with chronic liver disease to ask their
                                               doctor for advice about taking products                 1. Hepatotoxicity                                     doctor before using acetaminophen.
                                               containing OTC IAAA active                                                                                    FDA recognizes there is limited
                                                                                                          FDA tentatively concludes that
                                               ingredients.                                                                                                  information supporting the need for
                                                  FDA continues to believe that                        additional new labeling is needed for
                                                                                                       OTC drug products that contain                        different dose recommendations in
                                               acetaminophen and NSAIDs, when                                                                                people with liver disease. FDA seeks
                                               labeled appropriately and used as                       acetaminophen. Data from Lee (Ref. 6),
                                                                                                       a case series from the University of                  comment on the information this
                                               directed, are generally recognized as                                                                         warning should provide and encourages
                                               safe and effective OTC IAAA drugs for                   Pennsylvania Hospital (Ref. 4), and the
                                                                                                       FDA AERS database show that                           healthcare providers and researchers
                                               consumer self-use. However, the                                                                               who treat patients with chronic liver
                                               available evidence clearly indicates that               unintentional overuse of acetaminophen
                                                                                                       is associated with severe hepatic injury.             disease to provide information on how
                                               both drugs can cause serious side                                                                             much they recommend as an
                                               effects. When taken in excess amounts,                  One manufacturer provided calculations
                                                                                                                                                             appropriate dose and the basis for their
                                               acetaminophen can cause liver injury.                   of a ‘‘worst case’’ scenario for
                                                                                                                                                             recommendation.
                                               NSAIDs have the potential to cause GI                   acetaminophen hepatic failure deaths
                                               bleeding and renal (kidney) injury even                 using estimates by Lee (Ref. 70) and                  2. Other Labeling
                                               at OTC dosing levels.                                   calculated 213 deaths per year. FDA                      FDA also tentatively concludes that
                                                  When compared to the extensive use                   does not know the exact number of                     the name ‘‘acetaminophen’’ on the PDP
                                               of OTC acetaminophen and NSAID drug                     cases of liver failure or deaths related to           should be enhanced to allow consumers
                                               products, the incidence of injury                       unintentional acetaminophen overdose.                 to better identify acetaminophen
                                               appears relatively low. However, based                  FDA thinks that improved labeling may                 containing products among the many
                                               on the available evidence and the                       help prevent events that are catastrophic             products currently available on the OTC
                                               seriousness of the risks, FDA believes it               to the unintentional victims and their                market. First, FDA is proposing that the
                                               is necessary for consumers to be made                   family members. FDA has determined                    name be highlighted (e.g., in fluorescent
                                               aware of the possible serious side effects              that adding a liver warning is necessary              or color contrast to other information on
                                               associated with using these products.                   for safe and effective use of the drug and            the PDP) or in bold type so that the
                                               For many people, the risks are quite low                to reduce the number of unintentional                 name is prominent and stands out from
                                               because they use these products only                    overdoses. Thus, FDA is proposing a                   other text. Second, FDA is proposing
                                               occasionally. The risks may be greater                  ‘‘liver warning’’ stating use factors that            that the name have a size that is
                                               for people who use these products more                  could lead to liver injury.                           prominent compared to other printed
                                               frequently, have certain risk factors,                     FDA notes that NDAC recommended                    matter on the PDP. FDA’s regulation for
                                               and/or do not follow the labeling                       both an alcohol warning and a liver                   the statement of identity for OTC drug
                                               information on the package. FDA                         toxicity statement separate from the                  products in § 201.61(c) (21 CFR
                                               believes that providing additional                      alcohol warning for OTC drug products                 201.61(c)) states that ‘‘the statement of
                                               labeling information about how to                       containing acetaminophen. FDA has                     identity shall be presented in bold face
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                                               correctly use OTC drug products                         combined this information because it is               type on the PDP, shall be in a size
                                               containing acetaminophen and NSAIDs                     interrelated and a shorter warning saves              reasonably related to the most
                                               could reduce injuries and is necessary                  label space on products that already                  prominent printed matter on such panel
                                               for the products to be considered                       contain extensive labeling information.               ***.’’ FDA is proposing that
                                               generally recognized as safe and                        FDA believes that two, separate                       manufacturers determine the
                                               effective and not misbranded.                           warnings may be less likely to be read                prominence of the name
                                                  FDA plans to act on several fronts:                  and understood by consumers.                          ‘‘acetaminophen’’ on the PDP by


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                                               77332                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               selecting, from the two options that                    or older, who have had stomach ulcers                 acute reduction in renal blood flow and
                                               follow, the print size option that is                   or bleeding problems, or who use                      glomerular filtration, leading to renal
                                               greater:                                                corticosteroids or anticoagulants (Refs.              insufficiency. These cases are often
                                                 • The name ‘‘acetaminophen’’ is at                    10 and 55). Based on these studies, FDA               reversible. Although the
                                               least one-quarter as large as the size of               believes that people 60 years of age and              epidemiological data are limited and the
                                               the most prominent printed matter on                    older are at increased risk and is                    number of reported cases are rare
                                               the PDP; or                                             proposing to include this age group in                relative to their use, FDA believes it is
                                                 • The name ‘‘acetaminophen’’ is at                    the warning.                                          important to alert consumers about
                                               least as large as the size of the ‘‘Drug                   In September 1993, NDAC concluded                  underlying conditions that may increase
                                               Facts’’ title, as required in § 201.66(d)(2)            that the use of aspirin, ibuprofen, and               their risk if they take an NSAID without
                                               (21 CFR 201.66(d)(2)).                                  naproxen sodium increases the risk of                 first asking a doctor because of potential
                                                 Finally, FDA notes that NDAC                          UGIB in people who are heavy alcohol                  serious side effects.
                                               expressed concern about the lack of                     users or abusers. At the September 2002                  NDAC agreed with the OTC labeling
                                               standardized pediatric dosage                           meeting, during discussion of the                     proposed for ibuprofen in the Federal
                                               information, especially for infants under               relative risks for GI bleeding associated             Register of August 21, 2002, including
                                               2 years of age. FDA intends to address                  with the use of OTC NSAIDs, some                      the warning to ask a doctor before use
                                               this issue in another Federal Register                  NDAC members questioned whether the                   in the presence of high blood pressure,
                                               publication.                                            incidence of GI bleeding is increased by              heart or kidney disease, concomitant
                                                                                                       the concurrent use of NSAIDs and                      use of a diuretic, or if they are over 65
                                               B. Aspirin and Other NSAIDs                             alcohol. NDAC members were divided                    years of age. Based upon a further
                                               1. GI Bleeding                                          almost equally. Some members thought                  review of the literature that indicates
                                                                                                       that there was no clear evidence that                 that the risk is higher for people age 60
                                                  FDA tentatively concludes that                       alcohol potentiates the risk of bleeding              or older, FDA is proposing to lower the
                                               epidemiological data indicate a dose-                   in NSAID or aspirin users. They                       age from 65 years of age to 60 years of
                                               related risk for GI bleeding with                       proposed removal of the existing                      age.
                                               NSAIDs. The data demonstrate a slight                   alcohol warning. Other NDAC members                      Children’s NSAID products marketed
                                               increase in risk for GI bleeding at OTC                 suggested that the alcohol warning                    under an NDA already have warnings
                                               daily doses. Because many people use                    should remain in effect, but be                       regarding dehydration and fluid loss.
                                               OTC NSAIDs intermittently, the risk for                 separated from the GI bleeding warning.               FDA tentatively concludes that similar
                                               bleeding for the average person is quite                   Subsequently, FDA considered                       language is needed for children’s
                                               low. People who use NSAIDs for several                  NDAC’s recommendations and                            NSAIDs products marketed under the
                                               days may be at greater risk but it is still             evaluated the alcohol warning for OTC                 OTC drug monograph. There are,
                                               low compared to chronic NSAID users.                    drug products containing an NSAID.                    however, few case reports suggesting a
                                               People who have certain identifiable                    FDA did a new literature search,                      problem in adults. FDA is seeking
                                               risk factors (e.g., stomach ulcers or                   selecting new articles describing the                 comment on the need for similar
                                               bleeding problems, taking certain other                 relationship between alcohol use and                  language for adults. Although there are
                                               drugs or alcohol concurrently) are at                   the risk of GI bleeding in OTC IAAA                   few reported cases in adults, it is
                                               greater risk of GI bleeding when they                   users. After reviewing these articles                 anticipated that prostaglandin has
                                               take a product containing an NSAID.                     (Ref. 71), FDA finds that these studies,              similar effects on renal physiology.
                                               FDA believes that additional warnings                   despite some flaws in their design and
                                               alerting these people about these                                                                             3. Other Labeling
                                                                                                       methodology, suggest that combining
                                               potential risks and some of the                         NSAIDs with alcohol increases the risks                  FDA agrees with NDAC that the term
                                               symptoms associated with GI bleeding                    of a GI bleed. FDA has determined that                ‘‘NSAID’’ should be prominently
                                               could reduce morbidity from using                       it is necessary to retain a warning                   displayed in OTC drug product labeling
                                               these OTC NSAID drug products.                          regarding use of OTC NSAID drug                       so consumers are aware of the presence
                                                  Based on the NDAC’s                                  products with alcohol. FDA tentatively                of the ingredient in the product. The
                                               recommendations and the agency’s                        concludes that a warning about this risk              term should also be defined in the
                                               review of the literature, FDA has                       should be incorporated in a ‘‘Stomach                 labeling as ‘‘nonsteroidal anti-
                                               determined that additional new warning                  bleeding warning’’, in place of the                   inflammatory drug.’’ FDA tentatively
                                               labeling is needed to continue to                       current alcohol warning. Although                     concludes that the presence of an
                                               consider OTC NSAID products generally                   NDAC recommended that a GI bleeding                   ‘‘NSAID’’ ingredient in an OTC drug
                                               recognized as safe and effective. Such                  warning be distinct from a warning                    product should be prominently stated
                                               warnings should advise people not to                    against alcohol ingestion with NSAIDs,                on the PDP and in the Drug Facts
                                               take more than one product containing                   FDA is proposing to combine these two                 labeling.
                                               NSAIDs (aspirin, ibuprofen, naproxen,                   warnings to conserve labeling space and                  In section V.A.2 of this document,
                                               or others) and not to take more drug or                 avoid redundancy.                                     FDA discusses its proposed
                                               take the drug for a longer time than                                                                          requirements for the name
                                               recommended in product labeling.                        2. Renal Effects                                      ‘‘acetaminophen’’ to be prominently
                                               NDAC also acknowledged that people                         FDA tentatively concludes that people              presented on the PDP. FDA considers
                                               age 65 and older are at increased risk for              who get acute renal insufficiency from                the same degree of prominence
                                               GI bleed.                                               using NSAIDs generally have a pre-                    necessary to identify the presence of an
                                                  FDA subsequently reviewed the                        existing condition that will predispose               ‘‘NSAID’’ ingredient in an OTC IAAA
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                                               results of several large-scale clinical                 them to this insufficiency. There is a                drug product. Accordingly, FDA is
                                               studies, conducted in the United States                 pharmacological basis for this to occur.              proposing that the name of the NSAID
                                               and worldwide, and has established that                 Normal renal blood flow depends on                    ingredient and the word ‘‘(NSAID)’’ be
                                               use of NSAIDs is an important risk                      prostaglandin metabolism. NSAIDs                      highlighted (e.g., fluorescent or color
                                               factor for serious GI adverse events,                   inhibit renal prostaglandin production.               contrast) or in bold type, be in lines
                                               especially bleeding. These studies show                 In predisposed people, suppression of                 generally parallel to the base on which
                                               that the risk is higher for people age 60               prostaglandin production may result in                the package rests as it is designed to be


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                           77333

                                               displayed, and be in one of the                            • The presence of acetaminophen in                 3. For Acetaminophen Products Labeled
                                               following sizes, whichever is greater: (1)              the product must be prominently stated                Only for Children Under 12 Years of
                                               At least one-quarter as large as the size               on the PDP. The word ‘‘acetaminophen’’                Age
                                               of the most prominent printed matter on                 must appear highlighted (e.g.,                          Under proposed § 201.325(a)(1)(iv),
                                               the PDP, or (2) at least as large as the                fluorescent or color contrast) or in bold             the labeling would be required to
                                               size of the ‘‘Drug Facts’’ title, as                    type, be in lines generally parallel to the           include the following statement:
                                               required in § 201.66(d)(2). In the Drug                 base on which the package rests as it is                Liver warning: This product contains
                                               Facts labeling, FDA is proposing that                   designed to be displayed, and be in one               acetaminophen. Severe liver damage
                                               the active ingredient(s) section, as                    of the following sizes, whichever is                  may occur if the child takes
                                               defined in § 201.66(c)(2), be required to               greater: (1) At least one-quarter as large              • more than 5 doses in 24 hours
                                               contain the term ‘‘(NSAID)’’ after the                  as the size of the most prominent                       • with other drugs containing
                                               NSAID active ingredient with an                         printed matter on the PDP, or (2) at least            acetaminophen.
                                               asterisk statement at the end of the                    as large as the size of the ‘‘Drug Facts’’              This ‘‘Liver warning’’ must be the first
                                               active ingredient(s) section that defines               title, as required in § 201.66(d)(2).                 warning under the ‘‘Warnings’’ heading.
                                               the term ‘‘NSAID’’ as a ‘‘ * nonsteroidal                  • The presence of acetaminophen                      The labeling would also be required
                                               anti-inflammatory drug.’’                               must appear as part of the established
                                                  In addition, FDA has conducted a                                                                           to include the statements ‘‘Do not use
                                                                                                       name of the drug, as defined in § 299.4               with any other drug containing
                                               detailed review of available data                       (21 CFR 299.4).
                                               regarding the potential risks of serious                                                                      acetaminophen (prescription or
                                               cardiovascular events in patients                          • Combination products containing                  nonprescription). Ask a doctor or
                                               receiving COX–2 selective and non-                      acetaminophen and a non-analgesic                     pharmacist before using with other
                                               selective NSAIDs. FDA also held a joint                 ingredient(s) (e.g., cough-cold) must                 drugs if you are not sure’’ and ‘‘Ask a
                                               meeting of its Arthritis and Drug Safety                include the name ‘‘acetaminophen’’ and                doctor before use if the child has liver
                                               and Risk Management on February 16–                     the names of the other active ingredients             disease.’’
                                               18, 2005, to consider these issues. FDA                 in the product on the PDP. Only the                     FDA is aware that products labeled
                                               is currently considering whether                        name ‘‘acetaminophen’’ must appear                    for children only are sometimes used by
                                               additional labeling changes related to                  highlighted (e.g., fluorescent or color               adults who cannot take solid oral dosage
                                               these risks are warranted, and will                     contrast) or in bold type, and be in one              forms or who are taking a product
                                               address this in a future issue of the                   of the following sizes, whichever is                  marketed in children’s strengths.
                                               Federal Register.                                       greater: (1) At least one-quarter as large            Accordingly, FDA is proposing to
                                                                                                       as the size of the most prominent                     include the statement ‘‘this product
                                               VI. FDA’s Proposal                                      printed matter on the PDP, or (2) at least            does not contain directions or warnings
                                                  Based on the available evidence, FDA                 as large as the size of the ‘‘Drug Facts’’            for adult use’’ in bold type in the
                                               is proposing to amend its regulations                   title, as required in § 201.66(d)(2).                 labeling of these products under the
                                               and the OTC IAAA TFM to make a                          2. For Acetaminophen Products Labeled                 heading ‘‘Directions’’.
                                               number of changes. FDA is proposing                     for Adults Only                                       4. For Acetaminophen Products Labeled
                                               new labeling for OTC IAAA drug
                                                                                                                                                             for Adults and Children Under 12 Years
                                               products (proposed § 201.325). This                        Under proposed § 201.325(a)(1)(iii),
                                                                                                                                                             of Age
                                               labeling includes a number of important                 the labeling would be required to
                                               new warnings. To alert consumers to                     include the following statement:                         Under proposed § 201.325(a)(1)(v), the
                                               these new warnings, FDA is proposing                       Liver warning: This product contains               labeling would be required to include
                                               to require that the statement ‘‘See new                 acetaminophen. Severe liver damage                    all of the warnings for adults with the
                                               warnings information’’ appear on the                    may occur if you take                                 following modifications:
                                               PDP of all OTC IAAA drug products for                      • more than (insert maximum number                    Liver warning: This product contains
                                               a limited time after the effective date of              of daily dosage units) in 24 hours                    acetaminophen. Severe liver damage
                                               a final rule based on this proposal                                                                           may occur if
                                                                                                          • with other drugs containing
                                               (proposed § 201.325(b)).                                                                                         • adult takes more than [insert
                                                  The labeling statements in this                      acetaminophen
                                                                                                                                                             maximum number of daily dosage units]
                                               proposed rule are in the OTC Drug Facts                    • 3 or more alcoholic drinks every                 in 24 hours
                                               labeling format (see § 201.66), which is                day while using this product.                            • child takes more than 5 doses in 24
                                               being implemented for all OTC drug                         This ‘‘Liver warning’’ would be the                hours
                                               products. For ease of reading, the                      first warning under the ‘‘Warnings’’                     • taken with other drugs containing
                                               following descriptions of the proposed                  heading. For products that contain both               acetaminophen.
                                               labeling statements do not include the                  acetaminophen and aspirin, the ‘‘Liver                   • adult has 3 or more alcoholic drinks
                                               bracketed formatting instructions                       warning’’ would appear after the                      every day while using this product.
                                               included in the codified portion of this                ‘‘Reye’s syndrome’’ and ‘‘Allergy alert’’                This ‘‘Liver warning’’ must be the first
                                               document.                                               warnings in § 201.66(c)(5)(ii)(A) and                 warning under the ‘‘Warnings’’ heading.
                                                                                                       (c)(5)(ii)(B) and before the NSAID                    FDA is proposing to use the term ‘‘the
                                               A. Alcohol Warning                                      ‘‘Stomach bleeding warning’’ in                       user’’ instead of ‘‘you or the child’’ for
                                                 FDA is proposing to remove § 201.322                  proposed § 201.325(a)(2)(iii)(A).                     warnings applying to both children and
                                               of the regulations entitled ‘‘Over-the-                    The labeling would also be required                adults. The ‘‘ask a doctor’’ statement is
                                               counter drug products containing                        to include the statements ‘‘Do not use                modified to read: ‘‘Ask a doctor before
                                               internal analgesic/antipyretic active
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                                                                                                       with any other drug containing                        use if the user has liver disease.’’
                                               ingredients required alcohol warning.’’                 acetaminophen (prescription or
                                                                                                       nonprescription). Ask a doctor or                     C. Aspirin and Other NSAIDs
                                               B. Acetaminophen
                                                                                                       pharmacist before using with other                      The NSAID category includes, but is
                                               1. For All Acetaminophen Products                       drugs if you are not sure’’ and ‘‘Ask a               not limited to, aspirin, carbaspirin
                                                  Proposed § 201.325(a)(1)(i) includes                 doctor before use if you have liver                   calcium, choline salicylate, ibuprofen,
                                               the following provisions:                               disease.’’                                            ketoprofen, magnesium salicylate,


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                                               77334                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               naproxen sodium, and sodium                             2. For NSAID Products Labeled for                     inflammatory drug (NSAID), which may
                                               salicylate. In the Federal Register of                  Adults Only                                           cause stomach bleeding. The chance is
                                               August 21, 2002 (67 FR 54139 at 54159),                    Warnings for NSAIDS are proposed in                higher if the child:
                                               FDA proposed a number of warnings for                                                                            • has had stomach ulcers or bleeding
                                                                                                       § 201.325(a)(2)(iii). Some of the
                                               products containing ibuprofen if added                                                                        problems
                                                                                                       proposed warning statements are
                                               to the OTC IAAA drug products                                                                                    • takes a blood thinning
                                                                                                       discussed here.
                                               monograph. FDA is adding information                                                                          (anticoagulant) or steroid drug
                                                                                                          Stomach bleeding warning: This                        • takes other drugs containing an
                                               and further revising portions of some of                product contains a nonsteroidal anti-
                                               those warnings in this document and                                                                           NSAID (aspirin, ibuprofen, naproxen, or
                                                                                                       inflammatory drug (NSAID), which may                  others)
                                               proposing these warnings be applicable                  cause stomach bleeding. The chance is
                                               to all OTC NSAIDs.                                                                                               • takes more or for a longer time than
                                                                                                       higher if you:                                        directed.
                                               1. For All Products Containing NSAIDs                      • are age 60 or older                                 The ‘‘Stomach bleeding warning’’
                                                                                                          • have had stomach ulcers or                       would appear after the ‘‘Reye’s
                                                  Proposed § 201.325(a)(2)(i) includes                 bleeding problems                                     syndrome’’ and ‘‘Allergy alert’’
                                               the following provisions:                                  • take a blood thinning                            warnings in § 201.66(c)(5)(ii)(A) and
                                                  • The presence of an NSAID                           (anticoagulant) or steroid drug                       (c)(5)(ii)(B).
                                               ingredient in the product must be                          • take other drugs containing an                      The labeling would be required to
                                               prominently stated on the PDP. The                      NSAID (aspirin, ibuprofen, naproxen, or               include the following statement:
                                               name of the NSAID ingredient and the                    others)                                                  Ask a doctor before use if the child
                                               word ‘‘(NSAID)’’ must appear                               • have 3 or more alcoholic drinks                  has
                                               highlighted (e.g., fluorescent or color                 every day while using this product                       • stomach problems that last or come
                                               contrast) or in bold type, be in lines                     • take more or for a longer time than              back, such as heartburn, upset stomach,
                                               generally parallel to the base on which                 directed.                                             or stomach pain
                                               the package rests as it is designed to be                  This ‘‘Stomach bleeding warning’’                     • ulcers
                                               displayed, and be in one of the                         would appear after the ‘‘Reye’s                          • bleeding problems
                                               following sizes, whichever is greater: (1)              syndrome’’ and ‘‘Allergy alert’’                         • not been drinking fluids
                                               At least one-quarter as large as the size               warnings in § 201.66(c)(5)(ii)(A) and                    • lost a lot of fluid due to vomiting
                                               of the most prominent printed matter on                 (c)(5)(ii)(B). For products that contain              or diarrhea
                                               the PDP, or (2) at least as large as the                both acetaminophen and aspirin, the                      • high blood pressure
                                               size of the ‘‘Drug Facts’’ title, as                    acetaminophen ‘‘Liver warning’’ would                    • heart or kidney disease
                                               required in § 201.66(d)(2).                             appear before the NSAID ‘‘Stomach                        • taken a diuretic.
                                                                                                       bleeding warning.’’                                      The labeling would be required to
                                                  • For single ingredient products, the                                                                      include the statement:
                                               word ‘‘(NSAID)’’ must appear as part of                    The labeling would be required to
                                                                                                       include the following statement:                         Ask a doctor or pharmacist before use
                                               the established name of the drug, as                                                                          if the child is
                                               defined in § 299.4 of this chapter, or as                  Ask a doctor before use if you have
                                                                                                          • stomach problems that last or come                  • taking any other drug containing an
                                               part of the statement of identity of the                                                                      NSAID (prescription or
                                               drug, as defined in § 201.61 of this                    back, such as heartburn,
                                                                                                                                                                nonprescription)
                                                                                                          upset stomach, or stomach pain
                                               chapter. For example, either of the                                                                              • taking a blood thinning
                                               following would be acceptable:                             • ulcers
                                                                                                                                                             (anticoagulant) or steroid drug
                                                                                                          • bleeding problems                                   The labeling would also be required
                                                  • Ibuprofen Tablets (NSAID)                             • high blood pressure                              to include the statement:
                                                  Pain reliever/ fever reducer                            • heart or kidney disease                             Stop use and ask a doctor if
                                                  or                                                      • taken a diuretic                                    • the child feels faint, vomits blood,
                                                  • Ibuprofen Tablets                                     • reached age 60 or older.                         or has bloody or black stools. These
                                                                                                          The labeling would be required to                     are signs of stomach bleeding.
                                                  Pain reliever/ fever reducer (NSAID)                 include the statement:                                   • stomach pain or upset gets worse or
                                                  • Combination products containing                       Ask a doctor or pharmacist before use              lasts
                                               an NSAID and a non-analgesic                            if you are                                               FDA is aware that products labeled
                                               ingredient(s) (e.g., cough-cold) must                      • taking any other drug containing an              only for children are sometimes used by
                                               include the name of the NSAID                           NSAID (prescription or nonprescription)               adults who cannot take solid oral dosage
                                               ingredient and the names of the other                      • taking a blood thinning                          forms or who are taking a product
                                               active ingredients in the product on the                (anticoagulant) or steroid drug                       marketed in children’s strengths.
                                               PDP. The word ‘‘(NSAID)’’ must appear                      The labeling would be required to                  Accordingly, FDA is proposing to
                                               after either the name of the NSAID                      include the statement:                                include the statement ‘‘this product
                                               ingredient or the general                                  Stop use and ask a doctor if                       does not contain directions or warnings
                                               pharmacological (principal intended)                       • you feel faint, vomit blood, or have             for adult use’’ in bold type in the
                                               action of the NSAID ingredient (see                     bloody or black stools. These are signs               labeling of these products under the
                                               previous examples). Only the name of                    of stomach bleeding.                                  heading ‘‘Directions’’.
                                               the NSAID ingredient and the word                          • stomach pain or upset gets worse or
                                               ‘‘(NSAID)’’ must appear highlighted                     lasts                                                 4. For NSAID Products Labeled for
                                               (e.g., fluorescent or color contrast) or in                                                                   Adults and Children Under 12 Years of
                                                                                                       3. For NSAID Products Labeled Only for                Age
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                                               bold type, and be in one of the following
                                               sizes, whichever is greater: (1) At least               Children Under 12 Years of Age
                                                                                                                                                                Under proposed § 201.325(a)(2)(v), the
                                               one-quarter as large as the size of the                   Under proposed § 201.325(a)(2)(iv),                 labeling would be required to include
                                               most prominent printed matter on the                    the labeling would be required to                     all of the warnings for adults with the
                                               PDP, or (2) at least as large as the size               include the following statement:                      following modifications:
                                               of the ‘‘Drug Facts’’ title, as required in               Stomach bleeding warning: This                         Stomach bleeding warning: This
                                               § 201.66(d)(2).                                         product contains a nonsteroidal anti-                 product contains a nonsteroidal anti-


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77335

                                               inflammatory drug (NSAID), which may                    D. Requirements to Supplement                         effective than a single 650-mg dose. One
                                               cause stomach bleeding. The chance is                   Approved Applications                                 of the other studies failed to
                                               higher if the user:                                       Holders of approved applications for                demonstrate a dose response between
                                                  • has had stomach ulcers or bleeding                 OTC IAAA drug products who                            the two doses, and the last study failed
                                               problems                                                voluntarily implement the proposed                    to show separation of the active
                                                  • takes a blood thinning                             labeling changes in proposed                          treatments from placebo. The overall
                                               (anticoagulant) or steroid drug                         § 201.325(a) would be required to                     safety profile for the 1,000-mg dose was
                                                  • takes other drugs containing an                    submit supplements under § 314.70(c)                  similar to the 650-mg dose, with the
                                               NSAID (aspirin, ibuprofen, naproxen, or                 (21 CFR 314.70(c)), but could                         exception of a higher incidence of
                                               others)                                                 implement the proposed labeling                       dizziness. In 1975, FDA approved a 500-
                                                  • takes more or for a longer time than               without advance approval from FDA,                    mg immediate-release tablet. Data from
                                               directed                                                provided the labeling includes the                    two crossover bioequivalence studies
                                                  • is age 60 or older                                 information in proposed § 201.325(a).                 comparing two 500-mg capsules to two
                                                  • has 3 or more alcoholic drinks                                                                           500-mg tablets demonstrated the
                                                                                                       See section IX of this document on
                                               everyday while using this product.                                                                            bioequivalence of the two formulations
                                                                                                       voluntary implementation.
                                                  The ‘‘Stomach bleeding warning’’                                                                           (Ref. 3).
                                               would appear after the ‘‘Reye’s                         E. Regulatory Action                                     The IAAA Panel further evaluated
                                               syndrome’’ and ‘‘Allergy alert’’                           Proposed § 201.325(c) sets out the                 acetaminophen and recommended in its
                                               warnings in § 201.66(c)(5)(ii)(A) and                   implementation dates for the proposed                 1977 report (42 FR 35346) that
                                               (c)(5)(ii)(B).                                          labeling changes after publication of any             acetaminophen be generally recognized
                                                  FDA is proposing to use the term ‘‘the               final rule based on this proposal. See                as safe and effective. The IAAA Panel’s
                                               user’’ instead of ‘‘you or the child’’ for              section VIII.B of this document on                    evaluation of effectiveness was based on
                                               warnings applying to both children and                  marketing conditions.                                 data from a number of controlled and
                                               adults in the above and following                                                                             uncontrolled studies of the effectiveness
                                                                                                       F. Conforming Changes to the OTC                      of a variety of acetaminophen doses, i.e.,
                                               modified statements.
                                                                                                       IAAA TFM                                              300, 325, 330, 500, 600, 1,000, and 1,200
                                                  The labeling would be required to
                                               include the following statement:                           This proposed rule includes changes                mg (42 FR 35346 at 35412). However,
                                                                                                       to the OTC IAAA TFM in proposed                       the IAAA Panel’s evaluation did not
                                                  Ask a doctor before use if the user has
                                                                                                                                                             include an assessment of the relative
                                                  • stomach problems that last or come                 § 343.50. Proposed § 343.50(c)(1)(i),
                                                                                                       (c)(1)(iii), (c)(1)(iv)(A), (c)(1)(v)(A),             effectiveness of each of the dosage
                                               back, such as heartburn, upset stomach,
                                                                                                       (c)(1)(v)(B), (c)(1)(v)(C), (c)(1)(ix)(A),            strengths. The Panel determined the
                                               or stomach pain
                                                                                                                                                             maximum daily safe dosage to be not
                                                  • ulcers                                             (c)(1)(ix)(B), (c)(1)(ix)(C), (c)(1)(ix)(E),
                                                                                                       (c)(2)(i), (c)(2)(iii), (c)(2)(iv)(A),                greater than 4 g in a 24-hour period.
                                                  • bleeding problems                                                                                        Upon publication of that document,
                                                  • high blood pressure                                (c)(2)(v)(A), (c)(2)(v)(B) and (c)(2)(v)(C)
                                                                                                       (as proposed in 53 FR 46204 and 67 FR                 FDA permitted OTC marketing without
                                                  • heart or kidney disease                                                                                  an NDA provided the product was
                                                  • taken a diuretic                                   54139) would be amended and new
                                                                                                       paragraphs (b)(4)(i)(c) and (c)(3)(i)                 consistent with the IAAA Panel’s
                                                  • not been drinking fluids                                                                                 recommended labeling. FDA’s 1988
                                                  • lost a lot of fluid due to vomiting                through (c)(3)(v)(C) would be added to
                                                                                                       either include references to proposed                 TFM for OTC IAAA drug products
                                               or diarrhea                                                                                                   proposed to include acetaminophen as a
                                                  • reached age 60 or older                            § 201.325 and/or additional language to
                                                                                                       conform to that section.                              monograph ingredient (53 FR 46204 at
                                                  The labeling would be required to                                                                          46255). FDA revised the IAAA Panel’s
                                               include the statement:                                  VII. Additional Issues for Consideration              recommended dosing regimens but
                                                  Ask a doctor or pharmacist before use                                                                      maintained the maximum limit of 4 g in
                                               if the user is                                          A. Safe and Effective Daily
                                                                                                                                                             a 24-hour period.
                                                  • taking any other drug containing an                Acetaminophen Dose                                       To determine the maximum daily safe
                                               NSAID (prescription or nonprescription)                    In 1960, FDA first approved (under                 dosage (4 g of acetaminophen in a 24-
                                                  • taking a blood thinning                            the NDA process) a 325-mg immediate-                  hour period), the Panel reviewed
                                               (anticoagulant) or steroid drug                         release acetaminophen tablet                          numerous references that describe cases
                                                  The labeling would also be required                  formulation for OTC marketing in the                  of serious liver damage associated with
                                               to include the statement:                               United States. The recommended dose                   excessive use of acetaminophen (42 FR
                                                  Stop use and ask a doctor if                         was one to two tablets every 4 to 6                   35346 at 35413). Most of these cases
                                                  • the user feels faint, vomits blood, or             hours, with a maximum daily dose of                   were associated with single dose oral
                                               has bloody or black stools. These are                   3,900 mg in a 24-hour period (Ref. 3).                ingestions of greater than 15 g of
                                               signs of stomach bleeding.                                 In 1973, FDA approved (under the                   acetaminophen. Based on this
                                                  • stomach pain or upset gets worse or                NDA process) a 500-mg immediate-                      information, the Panel concluded that a
                                               lasts.                                                  release acetaminophen capsule                         single dose less than 15 g is not usually
                                                                                                       formulation for OTC marketing in the                  associated with serious liver injury. The
                                               5. Active Ingredients                                   United States. The sponsor’s rationale                Panel also noted that 15 g is 23 times
                                                 Under proposed § 201.325(a)(2)(v), the                for this product was that the higher                  the usual recommended dose of 650 mg
                                               active ingredient(s) section of the                     strength would have greater analgesic                 and approximately 4 times the
                                               product’s labeling, as defined in                       efficacy. Four double-blind, placebo-                 maximum recommended daily dose of 4
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                                               § 201.66(c)(2), would be required to                    controlled, post partum pain studies                  g. In estimating the safety margin, the
                                               contain the term ‘‘(NSAID)*’’ after the                 evaluated the effectiveness of a single               Panel decided the comparison with the
                                               NSAID active ingredient with an                         dose of two 500-mg capsules (1,000 mg)                single dose (650 mg) was probably more
                                               asterisk statement at the end of the                    to a single dose of two 325-mg tablets                appropriate than the comparison with
                                               active ingredient(s) section that defines               (650 mg) in 338 subjects. Two of the                  the daily therapeutic dose (4 g). The
                                               the term ‘‘NSAID’’ as a ‘‘* nonsteroidal                studies demonstrated that a single                    current information on unintentional
                                               anti-inflammatory drug.’’                               1,000-mg dose was significantly more                  overdose suggests that the margin of


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                                               77336                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               safety may be less than originally                      was unable to recommend a reduced                     enabled a better evaluation of chronic
                                               determined. The data on liver failure                   maximum daily acetaminophen dose for                  alcohol use and underlying alcohol-
                                               presented by Dr. Lee at the September                   alcohol abusers, because of a lack of                 induced liver abnormalities. Subjects
                                               2002 NDAC meeting and the adverse                       specific data.                                        with AST and ALT higher than 120 IU/
                                               event reports in the FDA AERS data                         One drug manufacturer issued a ‘‘Dear              L were excluded from the study, so no
                                               suggest daily doses less than 10 g,                     Doctor’’ letter to inform health                      evaluation of subjects with underlying
                                               ingested on consecutive days, presents a                professionals about the September 2002                liver damage evidenced by slight
                                               risk for liver injury in some individuals.              NDAC meeting (Ref. 72). The letter                    elevations of liver function tests could
                                                  FDA invites comment on whether                       stated: ‘‘The NDAC proceedings may                    be assessed. Such subjects may respond
                                               there are subpopulations of individuals                 generate media interest and, as a result,             differently than those with more
                                               who are more susceptible to developing                  people may contact you with questions                 substantial hepatic impairment. Other
                                               liver injury when taking                                about OTC pain relievers such as                      investigators have similarly criticized
                                               acetaminophen. The dosing information                   acetaminophen.’’ The letter summarized                the studies (Refs. 76 and 77). Assessing
                                               included in the AERS cases of                           the existing data that support the safety             the change in liver function tests after
                                               hepatotoxicity reported for                             of acetaminophen, including the                       drug administration may not adequately
                                               acetaminophen suggest that the median                   statement: ‘‘Prospective data indicate                support a conclusion that the drug is
                                               daily dose is in the 5- to 6-g range. FDA               that chronic alcoholics can take                      without risk of liver injury in this
                                               recognizes, however, that dosing                        recommended doses of acetaminophen                    population. If subpopulations of chronic
                                               information in the AERS reports is                      up to 4,000 mg/day without risk of liver              alcoholics are sensitive to lower doses
                                               sometimes inaccurate and is difficult to                injury.’’ The letter cited two references             of acetaminophen, this type of study
                                               validate. The information in the AERS                   from the medical literature to support                would be inadequate to make any
                                               cases of hepatotoxicity is adequate to                  the statement (Refs. 73 and 74). The                  assessment of risk.
                                               raise concerns that there may be                        letter continued: ‘‘Acetaminophen can                    FDA also finds that a 2-day treatment
                                               subpopulations at risk for developing                   be used safely, at recommended doses,                 period may be too short to deplete the
                                               hepatotoxicity with doses lower than                    by the occasional moderate consumer of                lowered hepatic gluthianone capacity in
                                               the currently labeled maximum daily                     alcohol.’’                                            alcoholic people. The 2-day regimen
                                               dose of 4 g. If such subpopulations can                    FDA has reviewed the two references
                                                                                                                                                             cannot be extrapolated into the
                                               be identified, the maximum daily dose                   (studies of hepatotoxicity of the
                                                                                                                                                             recommended 10-day dosing regimen in
                                               of 4 g may no longer be considered safe                 therapeutic dose of acetaminophen in
                                                                                                                                                             OTC drug product labeling. One
                                               for those individuals and should be                     people with alcohol abuse, conducted
                                                                                                                                                             individual agreed, stating that the
                                               lowered. If the at risk subpopulations                  by the same investigators). One (Ref. 73)
                                                                                                                                                             investigators gave no rationale for
                                               cannot be identified, or addressed                      is a full study report of 201 people (102
                                                                                                       on acetaminophen and 99 on placebo).                  dosing acetaminophen for only 2
                                               through appropriate labeling, and cases
                                                                                                       The other (Ref. 75) was an abstract                   consecutive days while the drug is
                                               of liver injury continue to be reported,
                                                                                                       describing a pilot trial with 60 people               approved for 4 g/day for 10 consecutive
                                               FDA may reconsider whether the
                                                                                                       (30 each on acetaminophen and                         days and commonly used for prolonged
                                               labeled maximum daily dose is still
                                                                                                       placebo). A full report of this study is              periods of time (Ref. 78). Further, the
                                               generally recognized as safe and
                                                                                                       not available (Ref. 75).                              individual stated that the lack of
                                               effective for use in the general
                                                                                                          Both studies were randomized,                      elevation in liver enzyme values after
                                               population.
                                                                                                       double-blind, placebo-controlled                      only 2 days of acetaminophen lends
                                               B. Daily Dose Recommendation for                        clinical trials conducted in an alcohol               little support to the authors’ conclusion
                                               Alcohol Abusers                                         detoxification center to evaluate the                 regarding its safety in alcoholic people.
                                                  Following publication of the IAAA                    hepatotoxicity of maximum therapeutic                 FDA’s detailed assessment of these
                                               TFM in 1988, FDA received a comment                     dosing of acetaminophen in long-term                  studies is on file in the Division of
                                               recommending that the maximum daily                     alcoholic subjects. In both studies, the              Dockets Management (Ref. 79).
                                               dose of acetaminophen be reduced from                   subjects were treated with the maximum                   FDA concludes that these studies do
                                               4 to 2 g per day for alcohol abusers. The               therapeutic dose of acetaminophen (1g                 not provide reliable evidence that
                                               comment did not provide any data to                     four times a day) for 2 days, followed by             people with chronic alcohol use can
                                               support a reduced maximum daily dose.                   a 2-day observation. The results showed               safely take 4 g/day of acetaminophen,
                                               In June 1993, NDAC considered: (1)                      that acetaminophen treatment did not                  particularly for up to 10 days in
                                               Identifying a population at risk in terms               significantly increase serum ALT,                     accordance with OTC drug product
                                               of alcohol consumption, e.g., people                    Aspartate Aminotransferase (AST), and                 labeling. Based on the data presented by
                                               who rarely drink, social drinkers, or                   International Normalized Ratio (INR), as              Dr. Lee on liver failure, the experience
                                               alcohol abusers, (2) whether the data are               compared to the placebo control. The                  in the University of Pennsylvania
                                               sufficient to support a reduced                         authors concluded that there was no                   Hospital series, and data from the AERS
                                               maximum daily dose for alcohol                          evidence that the daily maximum                       database, FDA believes that alcohol
                                               abusers, and (3) if yes, what the reduced               therapeutic dose of acetaminophen                     users are a significant percentage of
                                               maximum daily dose should be. NDAC                      caused liver injury in alcoholics.                    persons who develop severe liver injury.
                                               found the data insufficient and was                     However, FDA finds the data                           Acetaminophen products already have
                                               unable to recommend a reduced                           insufficient to support this conclusion.              an alcohol warning to alert consumers
                                               maximum daily acetaminophen dose for                       Neither study included an assessment               of the risk for developing
                                               alcohol abusers.                                        of the quantity, frequency, and duration              hepatotoxicity. It is important to
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                                                  At the September 19, 2002, NDAC                      of alcohol use by the subjects. Alcoholic             determine whether the labeling should
                                               meeting, FDA described cases of                         detoxification history and information                include a lower daily dose for chronic
                                               hepatotoxicity involving the use of                     on alcohol-related disorders, including               alcohol users. At this time, FDA is
                                               prescription combination (narcotic/                     more specific hepatic evaluations (such               seeking both comments and data to
                                               acetaminophen) products (Refs. 6 and                    as hepatic CYP2E1 p450 enzyme levels,                 support a specific dosage for
                                               7). Many of these cases involved people                 glutathione levels, or biopsy), were not              acetaminophen as safe and effective in
                                               with a history of alcohol abuse. NDAC                   reported. That information would have                 people who consume alcohol.


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                           77337

                                               C. Combinations With Methionine or                      methionine would prevent or reduce                    impaired survival in persons with HIV
                                               Acetylcysteine                                          acetaminophen-induced liver toxicity.                 disease, and (5) the effect of NAC
                                                  FDA is currently evaluating different                FDA seeks comments and data on this                   replacement therapy on clinical
                                               safety measures to reduce the relative                  issue.                                                outcomes in persons with HIV disease.
                                                                                                                                                                A comment (Ref. 88) disagreed with
                                               risks for hepatotoxicity associated with                D. Package Size and Configuration                     the petitioner’s assertions for the
                                               the use of acetaminophen.                               Limitations                                           following reasons:
                                               Theoretically, one method might be to                     At the September 19, 2002, NDAC                        • The available data do not
                                               administer acetaminophen and N-                         meeting, a representative from a                      demonstrate that acetaminophen
                                               acetylcysteine (NAC) together. NAC is a                 national consumer organization                        reduces total body or circulating GSH
                                               chemical produced by the body that                      reported that the UK implemented                      when taken as recommended.
                                               enhances the production of the enzyme                   package size restrictions on                             • There currently are no studies that
                                               glutathione. A small portion of                         acetaminophen. He noted that an early                 demonstrate that acetaminophen has
                                               acetaminophen undergoes cytochrome                      assessment of the effect of the package               any impact on the survival of HIV
                                               P450-mediated N-hydroxylation to form                   size restrictions in the UK shows                     patients.
                                               N-acetyl-p-benzoquinoneimine (NAPQI,                    decreases in total and severe                            • The depletion of hepatic GSH that
                                               a toxic metabolite of acetaminophen).                   acetaminophen overdoses, as well as                   occurs after acetaminophen overdose is
                                               Liver toxicity from acetaminophen                       decreases in acetaminophen related                    not related to plasma GSH levels.
                                               overdose depends in part on production                  toxicity leading to liver transplant or                  • The source of plasma GSH in
                                               of NAPQ to levels that exceed the ability               death. The representative did not                     humans is not clearly defined.
                                               of the normal hepatic detoxification                    provide any data to support his                          FDA finds that although data from in
                                               pathway to eliminate NAPQ.                              comments. FDA seeks comments on                       vitro and in vivo studies (Refs. 89
                                               Glutathione is produced predominantly                   package size and package configuration                through 96) have documented low
                                               in the liver and is an important                        limitations as a mechanism to increase                levels of GSH and its precursors in HIV
                                               detoxifier of NAPQ. In the event of                     safe use of acetaminophen products by                 infection, the effect of this deficiency on
                                               acetaminophen overdose in people with                   reducing overdose. Comments should                    survival has not been clearly
                                               enhanced activity of CYP 2E1                            address the possible impact of such                   established. Data from in vitro studies
                                               (alcoholics, or people using                            measures on unintentional and                         (Refs. 97 through 100) have
                                               anticonvulsants), glutathione liver                     intentional overdose.                                 demonstrated improvement in healthy
                                               stores are depleted. One substrate for                                                                        and HIV-infected T-cell functioning post
                                               glutathione synthesis is cysteine. NAC                  E. Label Warning for Individuals With                 exposure to NAC. However, these
                                               protects against liver damage in early                  Human Immunodeficiency Virus (HIV)                    findings have not been correlated with
                                               acetaminophen poisoning by production                      A citizen petition (Refs. 86 and 87)               survival from in vivo studies. While
                                               of cysteine, a glutathione precursor. The               requested that FDA consider the need                  some studies of the effects of NAC
                                               administration of precursors of cysteine,               for a warning about the increased risk of             administration in HIV-infected
                                               such as NAC or methionine, may                          liver injury from the use of                          individuals (Refs. 89, 90, and 101
                                               prevent depletion of glutathione and,                   acetaminophen by individuals infected                 through 104) have demonstrated an
                                               thus, liver injury (Refs. 80 and 81).                   with HIV. The request is based on the                 increase in GSH, the majority of studies
                                                  Scientific data supports the efficacy of             following reasoning:                                  were not designed to assess survival.
                                               treating acute acetaminophen overdose                      • Glutathione (GSH) deficiency is                     Herzenberg, et al. (Ref. 102) discussed
                                               with early administration of NAC (Refs.                 frequent in HIV-infected individuals.                 results from several studies in HIV-
                                               82 through 85). To determine whether                       • Acetaminophen depletes GSH                       infected patients that evaluated the
                                               there is any usage data of                              (essential for the detoxification of                  relationship between GSH levels and
                                               acetaminophen with NAC or                               acetaminophen’s toxic metabolite) and                 survival, the administration of NAC in
                                               methionine for the purposes of                          is potentially more toxic to GSH-                     patients with low GSH levels in whole
                                               prevention of liver toxicity, FDA                       deficient individuals.                                blood and in CD4 T cells, and the effect
                                               examined the literature from 1975 to                       • GSH deficiency is associated with                of NAC on survival in patients with low
                                               December 2002. FDA did not find any                     impaired survival in persons with HIV                 GSH levels in CD4 T cells. The
                                               articles that specifically addressed                    disease, and acetaminophen may further                presentation of data in the report made
                                               whether either combination (when used                   reduce survival by depleting GSH.                     it difficult to understand the study
                                               at the therapeutic dose level) would                       In support of this request, the                    design details. Other problems based on
                                               prevent liver toxicity.                                 petitioner (Ref. 86) provided published               the information presented included:
                                                  The UK is the only country where a                   studies of: (1) GSH and cysteine levels               Survival data was not collected in a
                                               combination product containing                          in plasma, peripheral blood monocytes                 significant proportion of the population
                                               acetaminophen and methionine is                         and lymphocytes, and in the pleural                   (17 percent), baseline characteristics of
                                               available. The marketed product                         fluid of HIV-positive individuals, and                the individuals in all of the trials were
                                               contains 500 mg acetaminophen and                       (2) the effects of GSH replacement in                 not presented, the use of antiviral
                                               100 mg methionine. One published                        model systems and HIV-infected                        treatments and other medications before
                                               study summarized the issues related to                  individuals. A subsequent submission                  and during the studies was not
                                               combining acetaminophen and                             (Ref. 87) provided a search of the                    provided, and NAC administration after
                                               methionine (Ref. 85). The authors                       worldwide literature that included                    8 weeks was not randomized. In their
                                               acknowledge that there are no data                      studies of: (1) Nonhepatic GSH levels in              conclusions, the authors recommend
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                                               available on the relative efficacy or the               numerous disease states, (2) the effects              that excessive exposure to
                                               prophylactic antidotal dose of                          of treatment with NAC or other GSH-                   acetaminophen be avoided in HIV-
                                               methionine for protecting the liver after               replenishing drugs in diseases and                    infected individuals. The report
                                               acetaminophen overdose in humans.                       conditions in which GSH is decreased,                 references acetaminophen overdose
                                                  At this time, FDA finds insufficient                 (3) the causes of GSH deficiency in                   leading to GSH deficiency as a basis to
                                               evidence that combinations of                           persons with HIV disease, (4) an                      support their recommendation.
                                               acetaminophen with NAC or                               association between GSH deficiency and                However, it does not provide sufficient


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                                               77338                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               information suggesting that intermittent                period of time (several months to years),             warfarin interaction occurs has yet to be
                                               or short-term use presents a problem in                 and used acetaminophen ‘‘regularly’’                  clearly identified (Refs. 119 and 120).
                                               HIV patients. FDA concludes that this                   instead of ‘‘intermittently’’ for                        The second updated literature review
                                               report does not provide a sufficient                    approximately 3 to 14 days prior to the               (Ref. 127) noted two additional case
                                               basis to restrict that use of                           discovery of their abnormally prolonged               controlled studies generated from
                                               acetaminophen in patients infected with                 INR or PT. The dosages of                             patient cohorts followed in
                                               HIV.                                                    acetaminophen reportedly ingested by                  anticoagulation clinics that were
                                                  Further, a search of FDA’s AERS                      these individuals ranged from 1.2 to                  published in the European literature
                                               database for hepatic adverse events in                  4.5g/day. FDA’s epidemiologists                       (Refs. 123 and 124). Both of these
                                               HIV-infected individuals who took                       attribute the small number of                         studies failed to document the existence
                                               acetaminophen failed to identify any                    postmarketing case reports collected to               of a possible drug-drug interaction in
                                               case reports which fit the search                       underreporting. We believe that the                   stable anticoagulated people treated
                                               parameters, i.e., acetaminophen, HIV                    actual number of cases is much higher,                with the warfarin analogues
                                               infection, and hepatotoxicity. Thus,                    based on the numbers of people who are                phenprocoumon or acenocoumarol and
                                               there is no clinical evidence of toxicity               treated with anticoagulant therapy.                   using acetaminophen concomitantly.
                                               or decrease survival that can be                           FDA’s epidemiologists also conducted                  The data generated from the literature
                                               attributed to the recommended use of                    two literature searches on this topic. In             searches are conflicting. Although many
                                               acetaminophen in HIV-infected                           the first (Ref. 126), FDA reviewed 11                 of the studies controlled for other
                                               individuals since GSH levels were never                 published articles describing three                   variables known to potentate warfarin’s
                                               validated to predict survival.                                                                                anticoagulant effect, it is not known if
                                                                                                       double-blind, placebo-controlled,
                                                  Given these facts, FDA does not                                                                            they all also controlled for life style
                                                                                                       randomized studies that demonstrated a
                                               consider the current data a sufficient                                                                        factors such as diet, the use of vitamins
                                               basis for a warning. However, the issues                prolongation of warfarin’s anticoagulant
                                                                                                       effect when acetaminophen was used                    and herbal medications, physical
                                               raised by the petition highlight the need                                                                     activity, concurrent illness, or liver
                                               for additional information or research to               concomitantly in a chronic manner
                                                                                                       (Refs. 110, 112, and 113). Two                        status. Extrapolating the clinical
                                               clarify whether acetaminophen poses                                                                           findings generated from the study by
                                               additional risk for certain population                  additional published double-blind,
                                                                                                       crossover studies showed that people on               Fattinger, et al. may not be applicable to
                                               subgroups (e.g., conditions in which                                                                          real life situations, since this trial was
                                               GSH is reduced). Therefore, FDA invites                 a stable warfarin dose who were acutely
                                                                                                       dosed with acetaminophen did not                      conducted in people where background
                                               the submission of data and comments                                                                           life style factors such as diet and
                                               on this issue.                                          experience any changes in their
                                                                                                       anticoagulant status (Refs. 111 and 117).             physical activity did not come into play
                                               F. Drug Interactions Between                            A prospective, case-control study                     due to the controlled study environment
                                               Acetaminophen and Warfarin                              looked at a cohort of people from an                  (Ref. 124). The study by van den Bemt,
                                                                                                       anticoagulant clinic, each of whom were               et al. may have also failed to
                                                  The labeling for a currently marketed
                                                                                                       noted to have an INR greater than 6 on                demonstrate the existence of an adverse
                                               warfarin-containing prescription drug
                                                                                                       a routine followup clinic visit. The                  drug-drug interaction associated with
                                               product lists acetaminophen as a drug
                                                                                                       study found that after controlling for                the concomitant use of acetaminophen
                                               that can increase warfarin’s
                                                                                                       other risk factors associated with                    with either of the warfarin analogues
                                               anticoagulant effect (Ref. 105). A
                                               reciprocal warning is not currently                     prolongation of anticoagulant status                  phenprocoumon or acenocoumarol,
                                               included on the consumer labeling for                   (i.e., medication use, recent diet, illness,          because these drugs may be metabolized
                                               any OTC drug products that contain                      alcohol consumption, and actual                       differently than warfarin (Ref. 123). FDA
                                               acetaminophen. To evaluate the need                     warfarin use), the use of acetaminophen               believes that the current available data
                                               for a consumer warning regarding co-                    was an independent dose-dependent                     do not demonstrate sufficient evidence
                                               administration of warfarin-containing                   risk factor for having an INR over 6 (P-              to warrant a consumer warning for
                                               drugs with acetaminophen, FDA                           value for trend <0.001). Other                        warfarin-acetaminophen interaction.
                                               considered postmarketing adverse event                  independent variables associated with                 However, we are seeking comments or
                                               case reports in our AERS database,                      the development of a prolonged INR                    data on whether additional labeling
                                               studies published in the worldwide                      were identified and included: Advanced                about this drug-drug interaction is
                                               literature (Refs. 106 through 125), and                 malignancy (odds ratio [OR], 16.4; 95                 warranted at this time.
                                               three consultative reviews (Ref. 126,                   percent confidence interval [CI], 2.4 to              VIII. Legal Authority
                                               127, and 128).                                          111.0), recent diarrheal illness (OR, 3.5;
                                                  In the consultative reviews, FDA                     95 percent CI, 1.4 to 8.6), decreased oral            A. Statement About Warnings
                                               epidemiologists identified a cumulative                 intake (OR, 3.6; 95 percent CI, 1.3 to                  Mandating warnings in an OTC drug
                                               total of 20 (3 probable and 17 possible)                9.7), ingesting a higher dose of warfarin             monograph does not require a finding
                                               postmarketing adverse event case                        than prescribed (OR, 8.1; 95 percent CI,              that any or all of the OTC drug products
                                               reports of prolongation of laboratory                   2.2 to 30.0), and taking new medications              covered by the monograph actually
                                               tests that monitor the ability of the                   known to interact with warfarin (OR,                  caused an adverse event, and FDA does
                                               blood to clot. These tests are the INR or               8.5; 95 percent CI, 2.9 to 24.7) (Ref. 113).          not so find. Nor does FDA’s requirement
                                               Prothrombin Time (PT). These reports                    The validity of this study’s findings was             of warnings repudiate the prior OTC
                                               occur in individuals treated chronically                subsequently questioned when it was                   drug monographs and monograph
                                               with warfarin who concomitantly took                    publicly criticized in the literature for             rulemakings under which the affected
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                                               acetaminophen and had minor or severe                   its flawed methodological design, such                drug products have been lawfully
                                               bleeding events. Of note, the only                      as the overlapping of risk factors in the             marketed. Rather, as a consumer
                                               background characteristics that were                    population studied (i.e., fever and the               protection agency, FDA has determined
                                               identifiable in these case reports were                 use of acetaminophen), and the lack of                that warnings are necessary to ensure
                                               that the individuals involved were                      reported adverse events (Refs. 115, 116,              that these OTC drug products continue
                                               generally elderly, had been on stable                   and 118). Additionally, the mechanism                 to be safe and effective for their labeled
                                               anticoagulant therapy for a prolonged                   by which a possible acetaminophen-                    indications under ordinary conditions


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77339

                                               of use as those terms are defined in the                drug products may implement the                       or more (adjusted annually for inflation)
                                               Federal Food, Drug, and Cosmetic Act                    proposed labeling without advance FDA                 in any one year.’’
                                               (the act). This judgment balances the                   approval provided the labeling includes                  FDA tentatively concludes that this
                                               benefits of these drug products against                 the information in proposed § 201.325.                proposed rule is consistent with the
                                               their potential risks (see 21 CFR                       A supplement must be submitted under                  principles set out in Executive Order
                                               330.10(a)).                                             § 314.70(c) to provide for the                        12866 and in these two statutes. This
                                                  FDA’s decision to act in this instance               implementation of such labeling. The                  proposed rule is not a significant
                                               need not meet the standard of proof                     supplement and its mailing cover                      regulatory action as defined by the
                                               required to prevail in a private tort                   should be clearly marked: ‘‘Special                   Executive Order and so is not subject to
                                               action (Glastetter v. Novartis                          Supplement—Changes Being Effected.’’                  review under the Executive Order. As
                                               Pharmaceuticals Corp., 252 F. 3d 986,                      FDA considers the proposed labeling                discussed in this section, FDA has
                                               991 (8th Cir. 2001)). To mandate                        in this document to be important to the               tentatively determined that this
                                               warnings, or take similar regulatory                    safe use of OTC IAAA drug products                    proposed rule will not have a significant
                                               action, FDA need not show, nor do we                    and strongly encourages manufacturers                 economic impact on a substantial
                                               allege, actual causation. For an                        of these products to voluntarily                      number of small entities. Because the
                                               expanded discussion of case law                         implement the proposed labeling                       rule does not impose any mandates on
                                               supporting FDA’s authority to require                   changes before FDA issues a final rule.               state, local or tribal governments, or the
                                               such warnings, see the final rule on                    However, voluntary compliance with                    private sector that will result in an
                                               ‘‘Labeling of Diphenhydramine-                          the proposed labeling in this document                expenditure in any one year of $100
                                               Containing Drug Products for Over-the                   is subject to the possibility that FDA                million or more, FDA is not required to
                                               Counter Human Use’’ (67 FR 72555,                       may revise the wording of some of the                 perform a cost-benefit analysis
                                               December 6, 2002).                                      proposed statements or changes, or not                according to the Unfunded Mandates
                                                                                                       require the statement or change, as a                 Reform Act. The current threshold after
                                               B. Marketing Conditions                                 result of comments filed in response to               adjustment for inflation is about $110
                                                  This proposal applies to all OTC                     this proposal. Because FDA wishes to                  million.
                                               internal analgesic/antipyretic drug                     encourage the voluntary use of the                       FDA estimates that manufacturers and
                                               products that contain an ingredient                     proposed labeling statements and                      marketers of OTC IAAA drug products
                                               included in proposed § 201.325(a).                      changes, FDA advises that                             would incur one-time compliance costs
                                               Upon issuance of a final rule, any new                  manufacturers will be given 18 months                 of $32 million in the first year to revise
                                               labeling will apply to any product that                 after publication of a final rule to use up           labeling to conform to the proposed
                                               is initially introduced or initially                    any labeling implemented in                           rule. The benefits of this proposed rule
                                               delivered for introduction into interstate              conformance with this proposal (see                   are based on estimated annual
                                               commerce. Such products would be                        section XV of this document).                         reductions from 1 to 3 percent in serious
                                               misbranded under section 502 of the act                                                                       illnesses and related hospital and
                                                                                                       X. Analysis of Impacts                                emergency room costs and in deaths
                                               (21 U.S.C. 352) and would be subject to
                                               regulatory action unless:                                  FDA has examined the impacts of this               related to unintentional overdosing. If 1
                                                  • Products marketed without an NDA                   proposed rule under Executive Order                   to 3 percent of these adverse events are
                                               include the required labeling within 12                 12866 and the Regulatory Flexibility Act              avoided, the monetized benefits would
                                               months after any final rule that is issued              (5 U.S.C. 601–612), and the Unfunded                  be $6 million to $17 million per year,
                                               based on this proposal.                                 Mandates Reform Act of 1995 (Public                   respectively. The present value of the
                                                  • Products marketed with an NDA                      Law 104–4). Executive Order 12866                     monetized benefits over a 10-year
                                               include the required labeling within 12                 directs agencies to assess all costs and              period is $41 million to $126 million
                                               months after any final rule that is issued              benefits of available regulatory                      assuming a 7-percent discount rate,1
                                               based on this proposal. The labeling                    alternatives and, when regulation is                  and $49 million to $147 million at a 3-
                                               may be put into use without advance                     necessary, to select regulatory                       percent discount rate. If we assume only
                                               FDA approval provided it includes the                   approaches that maximize net benefits                 a 1 percent reduction in the illnesses
                                               information described in the final rule.                (including potential economic,                        and fatalities analyzed, the benefits of
                                               Manufacturers should submit a                           environmental, public health and safety,              this proposed rule outweigh the costs.
                                               supplement under § 314.70(c).                           and other advantages; distributive                    We summarize the impacts in Table 10
                                                  If companies voluntarily implement                   impacts; and equity). Under the                       of this document.
                                               the labeling in this proposal before a                  Regulatory Flexibility Act, if a rule may                FDA notes that we lack the data
                                               final rule issues, FDA intends to provide               have a significant economic impact on                 needed to confidently predict a percent
                                               those companies 18 months to                            a substantial number of small entities,               reduction in serious cases related to
                                               implement the labeling in the final rule.               an agency must analyze regulatory                     unintentional overdosing. Because of
                                                                                                       options that would minimize any                       the uncertainty in these estimates, we
                                               IX. Voluntary Implementation                            significant impact of the rule on small               estimated an annual average number of
                                                 The labeling proposed in this                         entities. Section 202(a) of the Unfunded              adverse events that would need to be
                                               document represents a change from the                   Mandates Reform Act of 1995 requires                  avoided over a 10-year period to reach
                                               current labeling required for OTC IAAA                  that agencies prepare a written                       a breakeven point. Social benefits would
                                               drug products. Although FDA considers                   statement, which includes an                          equal the costs of compliance if the
                                               these proposed labeling changes to be                   assessment of anticipated costs and                   proposed rule prevented about 1 fatality
                                               very important, holders of approved                     benefits, before proposing ‘‘any rule that            each year (0.9 and 0.7 fatalities over 10
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                                               NDAs for OTC IAAA drug products will                    includes any Federal mandate that may                 years at a 7-percent and a 3-percent
                                               not be required to implement the                        result in the expenditure by State, local,            discount rate, respectively).
                                               proposed labeling at this time. However,                and tribal governments, in the aggregate,             Alternatively, if no fatalities are
                                               holders of approved NDAs for these                      or by the private sector of $100 million              avoided, the proposed rule would need


                                                 1Per the Office of Management and Budget (OMB)

                                               Circular A4, revised in 2003.


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                                               77340                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               to prevent about 475 hospitalizations                   discount rate, an average reduction of
                                               per year over the 10-year period at a 7-                410 hospitalizations per year is needed.
                                               percent discount rate. At a 3-percent

                                                                                                         TABLE 10.—SUMMARY OF IMPACTS
                                                                                        Benefits:                                                                      ($ Million)

                                                 Monetized 1 and 3-percent reduction in illnesses and mortality, per year                                                                       $5—$17
                                                 Present value over 10 years at 7 percent                                                                                                     $41—$126
                                                 Present value over 10 years at 3 percent                                                                                                     $49—$147

                                                 Costs:                                                                                                                                        ($ Million)
                                                 One-time label revision, first year                                                                                                                  $32



                                               A. Need for the Rule                                    immediate prescription container may                  for certain populations. Based on the
                                                  In September 2002, FDA’s NDAC                        not state that the product contains                   evidence discussed in this document,
                                               recommended changes to the labeling of                  acetaminophen or state the maximum                    FDA further finds that NSAIDs increase
                                               OTC IAAA drug products to better                        daily dose limit. Consumers may often                 the risk for GI adverse events and that
                                               inform consumers about the active                       fail to recognize the presence and                    without a new stomach bleeding
                                               ingredients and possible side effects                   amount of acetaminophen ingredients in                warning in the labeling for aspirin and
                                               caused by improper use. Although FDA                    OTC and prescription drug products.                   other NSAIDs the products would no
                                               considers acetaminophen to be safe and                  This lack of knowledge can result in a                longer be considered generally
                                               effective when labeled and used                         person taking two different products                  recognized as safe and effective and not
                                               correctly, taking too much can lead to                  containing acetaminophen                              misbranded for OTC use.
                                               liver damage and death. Similarly, the                  simultaneously. Moreover, many
                                                                                                       consumers are unaware that exceeding                     The purpose of this proposed rule is
                                               use of NSAIDs can lead to GI bleeding                                                                         to amend FDA’s OTC drug labeling
                                               and renal toxicity. The number of cases                 the recommended dosage for
                                                                                                       acetaminophen can lead to                             regulations and the TFM for OTC IAAA
                                               of injury reported is a very low
                                                                                                       unintentional overdosing and cause                    drug products to include new warnings
                                               percentage of the total use of OTC
                                                                                                       potential harm. Based on the evidence                 and other labeling requirements to
                                               acetaminophen and NSAID drug
                                               products. For many people, the risks are                discussed in this document, FDA finds                 advise consumers of potential risks and
                                               quite low because they use these                        that there is sufficient incidence of liver           when to consult a doctor. FDA is also
                                               products only occasionally. The risks                   damage associated with acetaminophen                  proposing to remove the alcohol
                                               may be greater for people who use these                 to warrant new labeling, and that                     warning in § 201.322 and incorporate
                                               products more frequently and/or do not                  without the new labeling,                             new alcohol-related warnings and other
                                               follow the labeling information on the                  acetaminophen products would no                       labeling for all OTC IAAA drug
                                               package. The risk of injury may be                      longer be considered generally                        products. FDA is proposing certain
                                               increased for certain populations and                   recognized as safe and effective and not              warning information targeted to age
                                               under certain conditions of use.                        misbranded for OTC use.                               specific populations. In addition, FDA
                                                  There are multiple reasons for                          Results of several large-scale clinical            is proposing that the presence of
                                               unintentional acetaminophen                             studies performed in the United States                acetaminophen or any NSAID would
                                               overdoses. First, acetaminophen is an                   and in other countries have established               appear prominently on the products’
                                               active ingredient in a wide variety of                  that the use of NSAIDs is an important                PDP. Table 11 presents an overview of
                                               both OTC and prescription drug                          risk factor for serious GI adverse events,            the proposed changes by type of
                                               products. For prescription products, the                especially bleeding. The risk is higher               product.

                                                                           TABLE 11.—OVERVIEW OF THE PROPOSED LABEL CHANGES BY PRODUCT TYPE
                                                                       Type of Product                                                                  Proposed Change

                                                 Acetaminophen                                                     Add a new warning to include information on serious liver injury. Include the name
                                                                                                                     acetaminophen [highlighted or in bold type, and in a prominent print size] on the
                                                                                                                     PDP.

                                                 NSAIDs (e.g., aspirin or ibuprofen)                               Add a new warning to include information on stomach bleeding. Include the name
                                                                                                                     of the NSAID ingredient [highlighted or in bold type] on the PDP. Include the
                                                                                                                     word ‘‘(NSAID)’’ [highlighted or in bold type, and in a prominent print size] on the
                                                                                                                     PDP either as part of the established name of the drug or after the general phar-
                                                                                                                     macological (principal intended) action of the NSAID ingredient.

                                                 Combination products containing acetaminophen or an               Include the name acetaminophen or the name of the NSAID ingredient [highlighted
                                                   NSAID and a nonanalgesic ingredient                               or in bold type, and in a prominent print size] and the names of the other active
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                                                                                                                     ingredients on the PDP. Products containing an NSAID ingredient must include
                                                                                                                     the word ‘‘(NSAID)’’ as stated under NSAIDS.




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                                                                  TABLE 11.—OVERVIEW OF THE PROPOSED LABEL CHANGES BY PRODUCT TYPE—Continued
                                                                       Type of Product                                                                  Proposed Change

                                                 All IAAA drug products                                            Remove the current alcohol warning in § 201.322, and incorporate new alcohol-re-
                                                                                                                    lated warnings format. For a specific period of time, add to the PDP the state-
                                                                                                                    ment ‘‘See new warnings information’’. We are proposing that this statement ap-
                                                                                                                    pear highlighted in the same way that the name ‘‘acetaminophen’’ or the pres-
                                                                                                                    ence of an NSAID appear on the PDP. The statement would appear highlighted
                                                                                                                    (e.g., fluorescent or color contrast) or in bold type; and be in one of the following
                                                                                                                    sizes, whichever is greater: (1) At least one-quarter as large as the size of the
                                                                                                                    most prominent printed matter on the PDP, or (2) at least as large as the size of
                                                                                                                    the ‘‘Drug Facts’’ title, as required in § 201.66(d)(2).



                                               B. Impact of the Rule                                   quantities) have been granted extensions               assumptions and methods for
                                                  FDA contracted with Eastern Research                 on compliance dates, many packaging                    calculating costs.
                                               Group, Inc. (ERG) to assess the costs and               alternatives now exist to assure                         ERG visited five stores—two major
                                               benefits of this proposed rule. The                     compliance.                                            chain drug stores and three convenience
                                               following is a summary of ERG’s                            Manufacturers routinely change labels               stores—to collect information on the
                                               analysis; the full report, including                    at varying intervals and have                          distribution of types of OTC IAAA drug
                                               details on assumptions, cost                            standardized procedures in place for                   product packaging. Roughly 80 percent
                                               calculations, and findings, is on file in               complying with FDA requirements. The                   of OTC IAAA drug products were
                                               the Division of Dockets Management                                                                             packaged in cartons and 20 percent in
                                                                                                       analysis assumes that one-half of the
                                               (Ref. 129).                                                                                                    containers. To assess the increase in
                                                                                                       manufacturers of OTC IAAA drug
                                                  Manufacturers and marketers of OTC                                                                          label space requirements, ERG
                                                                                                       products typically redesign their label
                                               IAAA drug products would incur one-                                                                            purchased 45 affected products, with an
                                                                                                       every 2 years, the remainder every 3                   emphasis on smaller packages.
                                               time costs to revise affected product
                                                                                                       years, based on consultant input. For
                                               labeling to comply with the proposed                                                                           1. Label Area Changes
                                                                                                       this analysis, ERG assumed that
                                               labeling changes. We assumed an
                                               implementation period of 12 months for                  manufacturers whose label redesign                       ERG collected and recorded
                                               one-time costs for a major labeling                     cycle is less than the implementation                  descriptive packaging information on
                                               revision. We estimated one-time costs                   period will not incur any regulatory                   the sampled products and measured
                                               for a major labeling revision using a                   costs. For example, if a company                       existing font size, labeling area and
                                               pharmaceutical labeling revision cost                   routinely revises its product labeling                 labeling text on packages, and the area
                                               model. This labeling model is described                 annually and is given at least that long               needed for replacement text. ERG then
                                               in detail in Appendix A of the ERG                      to incorporate the required changes,                   calculated the percentage increase in
                                               report (Ref. 129).                                      ERG judged that the regulatory revision                square millimeters (mm2) needed to
                                                  To develop the original model, FDA                   can be made at essentially no cost.                    accommodate the proposed labeling
                                               and ERG interviewed pharmaceutical                         The costs of labeling change depend                 changes. In all cases, ERG determined
                                               representatives from regulatory, legal,                 on the type of labeling (e.g., carton and              that the requirement to add active
                                               manufacturing controls, and labeling                    container label) and whether there is                  ingredient names on the PDP, while
                                               departments to collect information on                   sufficient labeling space to                           requiring major redesign in some cases,
                                               labeling change cost components, type                   accommodate the proposed changes.                      did not impose a change in the size of
                                               of personnel affected, and costs. The                   There are an estimated 22,500 OTC                      the PDP or the addition of non-standard
                                               model incorporates data on average                      IAAA drug product stockkeeping units                   labeling (such as adding a fifth carton
                                               industry costs by company size,                         (SKUs), split evenly among branded and                 panel or peelback label). ERG estimates
                                               including, where applicable,                            private labels, according to an industry               that the increase in existing label area
                                               modifications to packaging                              consultant.2 FDA assumes branded                       needed to accommodate the additional
                                               configurations. Industry consultants                    SKUs are distributed by firm size: 50                  proposed label warnings and text ranges
                                               also provided information on model                      percent small, 17 percent medium, and                  from 8 percent (acetaminophen) to 32
                                               inputs related to the OTC IAAA                          33 percent large. Based on consultant                  percent (ibuprofen).
                                               industry, the labeling revision process,                input, we assumed the distribution of                  2. Package size or type changes
                                               the costs of modifying labeling, and the                SKUs among OTC IAAA drug products
                                               frequency of packaging reconfiguration                                                                            ERG measured the available panels
                                                                                                       as follows: Acetaminophen, 45 percent;
                                               changes.                                                                                                       and white space on the 45 packages
                                                  The baseline for this proposed action                NSAIDS (except ibuprofen), 38 percent;                 sampled. If the available white space
                                               is full compliance with the format and                  ibuprofen, 15 percent; and combinations                was greater than the estimated increase
                                               content requirements for OTC drug                       of IAAAs (i.e., contain acetaminophen                  in space necessary to accommodate the
                                               product labeling in 21 CFR 201.66. In                   and aspirin), 2 percent. Cost estimates                new label warnings, ERG determined
                                               the final rule that established these                   are for small, medium, and large                       the product would not require an
                                               requirements on March 17, 1999 (64 FR                   branded companies, private label                       increase in carton or container size.
                                                                                                       companies, and by affected product
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                                               13254), FDA accounted for the total                                                                            Based on this review, ERG assumed that
                                               incremental costs to comply with                        group. The ERG report presents model                   all current packaging can accommodate
                                               requirements, including 6.0 font size                                                                          the required changes in this proposal
                                                                                                         2Estimates of affected SKUs are 18,000 (CDER)
                                               and related costs for increased package                                                                        without altering label sizes, package
                                                                                                       and from 20,000 to 25,000 (per industry consultant).
                                               size and longer labeling where                          This number of SKUs includes products marketed
                                                                                                                                                              sizes, or adding non-standard labels.
                                               applicable. FDA notes that although                     by manufacturers, repackers, relabelers, and           Therefore, ERG did not assign costs for
                                               some forms of packaging (for small                      distributors.                                          adjustments to packaging. Although


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                                               77342                 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               finding only a few small foil packs that                   Table 12 presents the estimated total                  over the relevant relabeling period is
                                               did not comply with the OTC Drug                         and annualized costs of compliance                       $15.2 million at a 7-percent discount
                                               Facts labeling requirements, ERG noted                   with the OTC IAAA drug product                           rate. The estimated average annualized
                                               that alternative types of packaging are                  proposed rule. The total estimated one-                  cost per SKU is $677 ($15.2 million/
                                               now available to replace the older                       time costs to revise labeling are $32.6                  22,500 SKUs).
                                               packages.                                                million. The estimated annualized cost

                                                                        TABLE 12.—ESTIMATED TOTAL AND ANNUALIZED COSTS OF COMPLIANCE ($ MILLION)
                                                                                                                                                 Product Type

                                                                                                                                                 NSAID (except                           Combinations of
                                                                                            Company Type             Acetaminophen                                       Ibuprofen
                                                                                                                                                  Ibuprofen)                                IAAAs

                                                 Small Brand                                                  2.2                     1.8                       0.7              0.1                   4.9

                                                 Medium Brand                                                 2.1                     1.8                       0.7              0.09                  4.7

                                                 Large Brand                                                  6.0                     5.1                       2.0              0.3                  13.3

                                                 Private Label                                                4.4                     3.7                       1.5              0.2                   9.7

                                                 Total                                                    14.7                       12.4                       4.9              0.7                  32.6



                                                 Total Annualized Costs (at 7-percent discount rate)

                                                 Small Brand                                                  1.0                     0.9                       0.3              0.05                  2.7

                                                 Medium Brand                                                 1.0                     0.8                       0.3              0.04                  2.2

                                                 Large Brand                                                  2.8                     2.4                       0.9              0.1                   6.2

                                                 Private Label                                                2.0                     1.7                       0.7              0.09                  4.5

                                                 Total                                                        6.9                     5.8                       2.3              0.3                  15.2



                                               C. Impact on Affected Sectors                            sales under $23 million. Generally, only                 labeling costs are absorbed by chain
                                                  Manufacturers of OTC drug products                    the largest supermarket and drug store                   stores and calculate impacts.
                                               are classified in North American                         chains (263 firms) or superstores (9                        To assess the impact on entities in the
                                               Industry Classification System (NAICS)                   firms) would have their own private                      pharmaceutical-manufacturing sector
                                               325412, pharmaceutical preparation                       label. ERG included only those largest                   (NAICS 325412), ERG adjusted SBA
                                               manufacturing. This classification code                  retail chains with annual sales of $100                  data on firm size and revenues to
                                               includes all manufacturers of                            million or more as having their own
                                                                                                                                                                 estimate average receipts per firm for
                                               prescription and OTC pharmaceutical                      private labels. Thus, FDA believes that
                                                                                                                                                                 the affected sector. ERG applied
                                               preparations, but does not include                       there are no small entities in these retail
                                                                                                                                                                 modeling assumptions to estimate the
                                               relabelers, repackers, and distributors.                 sectors that are affected. Marketers of
                                                                                                        private label OTC drug products are                      number of large and small affected
                                               The Small Business Administration                                                                                 firms. ERG further assumed the
                                               (SBA) defines a small business in this                   classified as follows:
                                                                                                           NAICS 446110, Pharmacies and drug                     distribution of all 22,500 affected SKUs
                                               industry classification code as one with                                                                          is one-third for large firms (producing
                                               fewer than 750 employees. In NAICS                       stores
                                                                                                           NAICS 445110, Supermarkets and                        either branded or private label products)
                                               325412, over 90 percent are considered
                                                                                                        other grocery stores                                     and two-thirds for small firms. To
                                               small entities. The affected industry is
                                               a subset of the OTC pharmaceutical                          NAICS 452910, Warehouse clubs and                     estimate the share of total compliance
                                               industry. This proposed rule affects an                  superstores.                                             costs for each size category, ERG
                                               estimated 258 manufacturers (of which                       Packaging and labeling services that                  distributed the SKUs attributed to small
                                               200 are small) of OTC IAAA drug                          contract with pharmaceutical                             businesses in the same proportion as
                                               products.                                                manufacturing firms may also be                          employment. The distribution of SKUs
                                                  Manufacturers often package private                   affected, but we assume manufacturers                    determines the distribution of
                                               label products, although some chains                     bear the costs of any labeling changes.                  compliance costs by employment size
                                               package their own brands. SBA                            Both the manufacturing and marketing                     category. Table 13 summarizes the
                                               considers the following to be small: (1)                 sectors will most likely share costs, but                estimated impacts for pharmaceutical
                                               Any pharmacy or drug store with                          the extent is not known. Therefore, this                 manufacturers, the total cost per firm
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                                               annual sales under $6 million, and (2)                   impact analysis first assumes that                       based on $677 per SKU, and the
                                               supermarkets and other grocery stores                    manufacturers absorb all of the labeling                 compliance costs as a percent of
                                               and warehouses and superstores with                      costs. We then assume that all private                   revenues.




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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                                 77343

                                                TABLE 13.—ESTIMATED IMPACTS ON PHARMACEUTICAL PREPARATION MANUFACTURING FIRMS BY SIZE (NAICS 325412)
                                                                                           Average Receipts         Assumed No. of                                      Total Firm Cost     Compliance Cost
                                                         Employment Size                                                                         SKUs per Firm
                                                                                            per Firm ($mil)             SKUs                                                ($000)1         as % of Receipts

                                                 <20                                                          1.7                    841                         9                    6.0           0.340%

                                                 20–99                                                       12.2                   2,591                     65                    43.8            0.361%

                                                 100–499                                                     61.9                   5,506                   148                    100.2            0.162%

                                                 500–749                                                 366.8                      6,062                   225                    151.9            0.041%

                                                 Total Small                                                 29.1               15,000                        75                    50.8            0.175%

                                                 >750                                                    947.8                      7,500                   130                     88.1            0.009%

                                                 Total                                                   109.6                  22,500                        87                    59.1            0.054%
                                                  1Number of SKUs x $677 per SKU.
                                                  Source: SBA, 1999 and ERG estimates.


                                                  Total estimated compliance costs per                 considered but rejected the following                     products. We used a value of $5 million
                                               firm ranged from $6,000 for firms with                  alternatives: (1) Not adding the new                      to represent the premature loss of a
                                               fewer than 20 employees to $152,000 for                 information to OTC IAAA drug product                      statistical life in previous analyses (see
                                               firms with 500 to 749 employees. The                    labeling, and (2) a longer                                66 FR 6137, January 19, 2001). We
                                               compliance cost as a percent of receipts                implementation period. FDA does not                       quantified the related hospital and
                                               is less than 1 percent for all firms; 0.18              consider either of these approaches                       emergency room costs, estimated related
                                               percent for all small firms and 0.01 for                acceptable because they do not assure                     morbidity costs, applied a value of $5
                                               large firms. This estimate of impacts is                that consumers will have the most                         million to the premature loss of a
                                               somewhat understated because the                        current labeling information needed for                   statistical life, and estimated annual
                                               census data used to derive estimates                    the safe and effective use of these                       savings if 1 to 3 percent of these adverse
                                               includes both OTC and prescription                      products. FDA considers this proposed                     events and deaths are avoided (Ref.
                                               drug manufacturers. However, no                         rule the least burdensome alternative                     129).
                                               alternative revenue and employment                      that meets the public health objectives
                                               size information for affected product                   of this rule.                                                We lack evidence to predict with
                                               lines is available. We tentatively                                                                                certainty a specific level of reduction in
                                               conclude that this estimate of the                      E. Benefits                                               adverse events. Nonetheless, we believe
                                               impacts of the proposed rule does not                      FDA’s proposed requirements are                        that presenting consumers with
                                               constitute a significant economic impact                intended to enhance consumer                              improved label warnings and more
                                               on a substantial number of small                        awareness and knowledge of the active                     prominently displaying the active
                                               entities.                                               ingredient in OTC IAAA drug products.                     ingredients on the PDP will promote
                                                  In a similar analysis, we assume chain               These new proposals include:                              safer use of OTC IAAA drug products.
                                               stores absorb costs for all 11,250 private                 • New label warnings                                   Specifically, prominent display of the
                                               label SKUs. Compliance costs as a                          • Age specific information                             active ingredients on the PDP would
                                               percent of receipts are less than 0.001                    • Advising consumers of potential                      alert consumers to the presence of the
                                               percent for all of the affected sectors:                risks and when to consult a doctor                        active ingredients in OTC IAAA drug
                                               Pharmacies, drug stores, superstores,                      • Prominent display of active                          products and help minimize the risks of
                                               supermarkets, and other grocery stores.                 ingredients on the PDP                                    unintentional overdosing. The revised
                                               No small entities are affected.                            The revised alcohol statements are                     warnings are intended to assist
                                                  Manufacturers routinely change labels                intended to provide clearer warnings to                   consumers, including higher risk
                                               at varying intervals and have                           high-risk individuals about product use.                  individuals, to use OTC IAAA drug
                                               standardized procedures in place for                    The overall intent of these proposed                      products more safely and lead to at least
                                               complying with FDA requirements. The                    requirements is to reduce the liver
                                                                                                                                                                 a modest reduction in unintentional
                                               proposed rule would not require any                     damage and GI bleeding episodes that
                                                                                                                                                                 overdosing.
                                               new reporting and record keeping                        occur due to unintentional overdosing
                                               activities and no additional professional               with these drugs. The proposed                               Table 14 summarizes the baseline and
                                               skills are needed. There are no other                   requirements are also intended to                         estimates of the number of avoidable
                                               Federal rules that duplicate, overlap, or               reduce the incidence of adverse health                    hospitalizations and emergency room
                                               conflict with the proposed rule; FDA is                 outcomes among high-risk                                  visits, the average cost per case, and
                                               proposing to remove the existing                        subpopulations consuming proper doses                     potential savings from events avoided.
                                               alcohol warning in § 201.322.                           of OTC IAAA drug products (e.g.,                          These data do not include reported
                                                                                                       people with liver disease or prone to GI                  cases of intentional overdosing. Based
                                               D. Alternatives                                         bleeding).                                                on the total monetized costs per adverse
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                                                 FDA does not believe that there are                      To estimate the benefits of this                       health outcome and the number of cases
                                               any alternatives to the proposed rule                   proposed rule, we developed baseline                      estimated to be avoided each year (from
                                               that would adequately provide for the                   information on the frequency of                           1 to 3 percent), the total monetized
                                               safe and effective use of OTC drug                      hospitalizations, emergency room visits,                  benefits of illness avoided range from
                                               products containing IAAA active                         and deaths related to unintentional                       $0.6 million to $1.8 million per year
                                               ingredients. Nonetheless, FDA                           overdosing with OTC IAAA drug                             ($592,600 to $1,777,900).



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                                               77344                  Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                                   TABLE 14. —SUMMARY OF ANNUAL MONETIZED BENEFITS OF ILLNESSES AVOIDED ASSOCIATED WITH THE PROPOSED
                                                                                            RULE (2001 $)
                                                                                                                Total Monetized         Potentially Pre-      Annual Number of             Total Annual Mone-
                                                   Adverse                                  Willing to Pay
                                                                     Hospital Costs                             Value of Illness       ventable Baseline     Cases Avoided Due to           tized Benefits of Ill-
                                                 Health Event                              to Avoid Illness         Avoided            Cases per Year(1)       Proposed Rule(2)            ness Avoided ($000)

                                                 Minor drug
                                                   toxicity or
                                                   emergency
                                                   room visits                   $209                  $301                  $510                   3,380                     34–101                 $17.2–$51.7

                                                 Acetamino-
                                                   phen poi-
                                                   soning epi-
                                                   sode with
                                                   hospitaliza-
                                                   tion                        $8,579                $2,000                $10,579                  3,424                     34–103             $362.2–$1,086.8

                                                 NSAID poi-
                                                  soning epi-
                                                  sode with
                                                  hospitaliza-
                                                  tion                         $8,579                  $357                 $8,936                  2,269                         23–68           $202.8–$608.3

                                                 Acute renal
                                                   failure with
                                                   hospitaliza-
                                                   tion                       $22,251        Not Estimated                 $22,251                       5                  0.05–0.15                  $1.1–$3.3

                                                 Acute renal
                                                   failure with
                                                   dialysis                   $22,251        Not Estimated                 $22,251                     0.7               0.007–0.021                   $0.2–$0.5

                                                 GI bleeding                  $14,653                  $357                $15,010                     61                     0.6–1.8                 $9.2–$27.5

                                                 Total mone-
                                                   tized ben-
                                                   efit of ill-
                                                   ness avoid-
                                                   ed                              NA                    NA                    NA                      NA                           NA           $592.6–$1,777.9
                                                 (1) The number of potentially preventable baseline cases per year is derived from data on emergency department and hospital cases of over-
                                               dosing, poisoning, or other serious adverse outcomes associated with acetaminophen and NSAID use, adjusted to estimate only unintentional
                                               cases.
                                                 (2) Assumes this proposed rule would reduce annual adverse event cases by 1 to 3 percent.
                                                 Source: FDA Section III.B.2 of this document and ERG report (Ref. 129).


                                                  In addition to estimating the value of                 benefits associated with preventing 1 to               from reduced hospital costs and deaths
                                               preventing adverse drug events that                       3 fatalities to be $5 to $15 million                   avoided, from $5.6 to $16.8 million,
                                               result in emergency department or                         annually ($2001).                                      would accrue each year. Over a 10-year
                                               hospitalization, we consider the annual                      If the proposed improved labeling and               period, the $5.6 to $16.8 million per
                                               number of deaths related to                               warnings reduced serious adverse                       year in benefits has a present value of
                                               unintentional acetaminophen                               events by 1 to 3 percent each year, the                $41.2 to $126.1 million at a discount
                                               overdoses. FDA estimates that from                        total monetized value of preventing                    rate of 7 percent, and a present value of
                                               1996 to 1998, an annual average of 99                     illness and fatalities because of                      $49.1 to $147.4 million at a discount
                                                                                                         improved labeling and warnings would
                                               adult deaths were related to                                                                                     rate of 3 percent. Thus, the benefits of
                                                                                                         be $5.6 million to $16.8 million per
                                               unintentional acetaminophen overdoses                                                                            this proposed rule, assuming a 1-percent
                                                                                                         year, respectively. These benefits are
                                               (see section III.B.2 of this document and                 presented in 2001 dollars.                             reduction in current levels of adverse
                                               the ERG report (Ref. 129)). We assume                        Benefit Cost Comparison. Industry                   health outcomes associated with the use
                                               the proposed rule would reduce                            would incur the one-time costs of the                  of OTC IAAA drug products, will more
                                               fatalities by 1 to 3 percent annually.                    proposed rule of $32.6 million in the                  than offset the costs of the proposed
                                               Applying a value of $5 million for each                   first year. In 2001, the costs were $32.0              rule. Table 15 summarizes the estimated
                                               fatality prevented, we estimate the total                 million. However, the estimated savings                benefits and costs of this proposed rule.

                                                                                                           TABLE 15.—SUMMARY OF IMPACTS
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                                                                                              Benefits/Costs                                                                        ($Million)

                                               Benefits:

                                               Monetized 1 and 3 percent reduction in illnesses and mortality, per year                                                            $5.6–$16.8
                                               Present value over 10 years at 7 percent                                                                                            $41–$126



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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                              77345

                                                                                                  TABLE 15.—SUMMARY OF IMPACTS—Continued
                                                                                            Benefits/Costs                                                                     ($Million)

                                               Present value over 10 years at 3 percent                                                                                        $49–$147

                                               Costs:

                                               One-time label revision, first year                                                                                              $32.6



                                                  Break-even Analysis. FDA notes that                  evaluate any comments and supporting                  503(f)(1)(A); and (2) that is different from or
                                               we lack the data needed to confidently                  data that are received and will reassess              in addition to, or that is otherwise not
                                               predict a percent reduction in serious                  the economic impact of this rulemaking                identical with, a requirement under this Act,
                                               cases related to unintentional                          in the preamble to any final rule.                    the Poison Prevention Packaging Act of 1970
                                               overdosing. Because of the uncertainty                                                                        (15 U.S.C. 1471 et seq.), or the Fair Packaging
                                                                                                       XI. Paperwork Reduction Act of 1995                   and Labeling Act (15 U.S.C. 1451 et seq.). *
                                               in these estimates, we estimated an
                                               annual average number of adverse                           FDA tentatively concludes that the                 **
                                               events that would need to be avoided                    labeling requirements proposed in this                   Currently, this provision operates to
                                               over a 10-year period to reach a                        document are not subject to review by                 preempt States from imposing
                                               breakeven point (i.e., the cost of                      the Office of Management and Budget                   requirements related to the regulation of
                                               compliance/present value of avoiding                    because they do not constitute a
                                                                                                                                                             nonprescription drug products. (See
                                               one death each year for 10 years). The                  ‘‘collection of information’’ under the
                                                                                                                                                             section 751(b), (c), (d), and (e) of the act
                                               proposed rule would need to prevent                     Paperwork Reduction Act of 1995 (44
                                                                                                       U.S.C. 3501 et seq.). Rather, the                     for the scope of the express preemption
                                               about 1 fatality each year over 10 years                                                                      provision, the exemption procedures,
                                               [0.9 fatality ($32/$37.6 million at a 7-                proposed labeling statements are public
                                                                                                       disclosures of information originally                 and the exceptions to the provision.)
                                               percent discount rate) and 0.7 fatality                                                                       This proposed rule, if finalized as
                                               ($32/$43.9 million at a 3 percent                       supplied by the Federal Government to
                                                                                                       the recipient for the purpose of                      proposed, would amend the labeling for
                                               discount rate)]. Alternatively, if no
                                                                                                       disclosure to the public (5 CFR                       over-the-counter IAAA drug products to
                                               fatalities are avoided, the proposed rule
                                                                                                       1320.3(c)(2)).                                        include new warnings and other
                                               would need to prevent about 476
                                                                                                                                                             labeling requirements advising
                                               hospitalizations ($32 million/$67,000)                  XII. Environmental Impact
                                               each year over the 10-year period. This                                                                       consumers about potential risks and
                                               estimate uses the present value of the                     FDA has determined under 21 CFR                    when to consult a doctor. Although any
                                               lowest benefit category of poisoning                    25.31(a) that this proposed action is of              final rule would have preemptive effect,
                                               episode with hospitalizations, $8,936                   a type that does not individually or                  in that it would preclude States from
                                               per episode over 10 years at a 7-percent                cumulatively have a significant effect on             issuing requirements related to the
                                               discount rate. At a 3 percent discount                  the human environment. Therefore,                     labeling of IAAA drug products that are
                                               rate, an average of 407 hospitalizations                neither an environmental assessment                   different from or in addition to, or not
                                               ($32 million/$79,000) would need to be                  nor an environmental impact statement                 otherwise identical with a requirement
                                               avoided annually over the period.                       is required.                                          in the final rule, this preemptive effect
                                                  Although we lack evidence to predict                 XIII. Federalism                                      is consistent with what Congress set
                                               with certainty a specific level of                                                                            forth in section 751 of the act. Section
                                                                                                          FDA has analyzed this proposed rule
                                               reduction in adverse events, if we                                                                            751(a) of the act displaces both state
                                                                                                       in accordance with the principles set
                                               assume only a 1-percent reduction in                    forth in Executive Order 13132. FDA                   legislative requirements and state
                                               the illnesses and fatalities analyzed, the              has determined that the proposed rule,                common law duties. We also note that
                                               benefits of this proposed rule outweigh                 if finalized as proposed, would have a                even where the express preemption
                                               the costs. FDA finds that this proposed                 preemptive effect on State law. Section               provision is not applicable, implied
                                               rule will enhance public health and                     4(a) of the Executive Order requires                  preemption may arise. See Geier v.
                                               promote the safer use of OTC IAAA                       agencies to ‘‘construe* * *a Federal                  American Honda Co., 529 U.S. 861
                                               drug products.                                          statute to preempt State law only where               (2000).
                                                  This economic analysis, together with
                                                                                                       the statute contains an express                          FDA believes that the preemptive
                                               other relevant sections of this
                                                                                                       preemption provision or there is some                 effect of the proposed rule, if finalized
                                               document, serves as FDA’s initial
                                                                                                       other clear evidence that the Congress                as proposed, would be consistent with
                                               regulatory flexibility analysis, as
                                                                                                       intended preemption of State law, or                  Executive Order 13132. Section 4(e) of
                                               required under the Regulatory
                                                                                                       where the exercise of State authority                 the Executive Order provides that
                                               Flexibility Act.
                                                  FDA invites public comment                           conflicts with the exercise of Federal                ‘‘when an agency proposes to act
                                               regarding any significant economic                      authority under the Federal statute.’’                through adjudication or rulemaking to
                                               impact that this rulemaking would have                  Section 751 of the Federal Food, Drug,                preempt State law, the agency shall
                                               on affected manufacturers of these OTC                  and Cosmetic Act (act) (21 U.S.C. 379r)               provide all affected State and local
                                               IAAA drug products. Comments                            is an express preemption provision that               officials notice and an opportunity for
                                                                                                       applies to nonprescription drugs.
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                                               regarding the impact of this rulemaking                                                                       appropriate participation in the
                                               should be accompanied by appropriate                    Section 751(a) of the act (21 U.S.C.                  proceedings.’’ FDA is providing an
                                               documentation. FDA is providing 150                     379r(a)) provides that:                               opportunity for State and local officials
                                                                                                         * * no State or political subdivision of a
                                               days from the date of publication of this               State may establish or continue in effect any
                                                                                                                                                             to comment on this rulemaking, and
                                               proposed rule in the Federal Register                   requirement— * * * (1) that relates to the            will conduct outreach to State and local
                                               for comments on this subject to be                      regulation of a drug that is not subject to the       governments or organizations
                                               developed and submitted. FDA will                       requirements of section 503(b)(1) or                  representing them.


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                                               77346                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               XIV. Request for Comments                               mailed comments, except that                          dockets/ac/02/slides/3882S1_05_Nourjah-
                                                                                                       individuals may submit one paper copy.                Ahmad-Karwoski_files/frame.htm.
                                                  In addition to requesting general                                                                             8. Weaver, J. P., ‘‘OTC NSAID and ASPIRIN
                                               comments on the proposal and the                        Comments are to be identified with the
                                                                                                                                                             GI Bleeding: Analysis of Spontaneous
                                               economic analysis, we are seeking                       docket number found in brackets in the
                                                                                                                                                             Reports,’’ presentation at September 20,
                                               comment on the following specific                       heading of this document and may be                   2002, NDAC meeting, transcript http://
                                               issues identified in the description of                 accompanied by a supporting                           www.fda.gov/ohrms/dockets/ac/02/
                                               the proposed rule (presented here for                   memorandum or brief. Received                         transcripts/3882T2.htm and slides http://
                                               the convenience of the reader):                         comments may be seen in the Division                  www.fda.gov/ohrms/dockets/ac/02/slides/
                                                                                                       of Dockets Management between 9 a.m.                  3882S2_03_Weaver_files/frame.htm.
                                                  1. Both comment and data on whether                                                                          9. Cryer, B., ‘‘Risks of NSAIDS: Focus on
                                               adult NSAID products should contain a                   and 4 p.m., Monday through Friday.
                                                                                                                                                             GI Risks of Over-the-Counter NSAIDs,’’
                                               warning regarding fluid loss or                         XV. Proposed Effective and Compliance                 presentation at September 20, 2002, NDAC
                                               dehydration similar to children NSAID                   Dates                                                 meeting, transcript http://www.fda.gov/
                                               products (see section V.B.2 of this                                                                           ohrms/dockets/ac/02/transcripts/3882T2.htm
                                               document).                                                 Because of the importance of the                   and slides http://www.fda.gov/ohrms/
                                                  2. Appropriate approaches to reduce                  proposed labeling to the safe use of OTC              dockets/ac/02/slides/
                                               unintentional acetaminophen overdose                    IAAA drug products, FDA is proposing                  3882S2_04_CRYER_files/frame.htm.
                                                                                                       that any final rule that may publish                    10. Garcia Rodriguez, L. A. et al, ‘‘Risk of
                                               (see section VII.A of this document).
                                                                                                       based on this proposal become effective               Upper Gastrointestinal Bleeding and
                                                  3. Whether more specific directions,                                                                       Perforation Associated With Individual Non-
                                               such as those currently required for                    12 months after its date of publication
                                                                                                                                                             Steroidal Anti-Inflammatory Drugs,’’ Lancet,
                                               OTC drug products containing                            in the Federal Register. Manufacturers                343: 769–772, 1994, correction 343: 1048,
                                               ibuprofen, should be considered for                     who voluntarily implement the labeling                1994.
                                               acetaminophen (see section VII.A of this                included in this proposal before the                    11. Gutthann, S. P., L. A. Rodriquez, and
                                               document).                                              final rule is published will have 18                  D. S. Raiford, ‘‘Individual Nonsteroidal Anti-
                                                  4. Both comment and data on whether                  months after the date of publication of               inflammatory Drugs and Other Risk Factors
                                               there are specific populations of people                the final rule in the Federal Register to             for Upper Gastrointestinal Bleeding and
                                               for whom the maximum daily dose for                     be in compliance with that final rule.                Perforation,’’ Epidemiology, 8(1):18–24, 1997.
                                                                                                                                                               12. Shorr, R. I. et al, ‘‘Concurrent Use of
                                               acetaminophen is not safe and effective                 XVI. References                                       Nonsteroidal Anti-inflammatory Drugs and
                                               and should be lowered (see section                                                                            Oral Anticoagulants Places Elderly Persons at
                                               VII.A of this document).                                  The following references are on                     High Risk for Hemorrhagic Peptic Ulcer
                                                  5. Both comment and data on specific                 display in the Division of Dockets                    Disease,’’ Archives of Internal Medicine,
                                               dosage for safe and effective use of                    Management (see ADDRESSES), under                     153:1665–1670, 1993.
                                               acetaminophen in people who consume                     Docket No. 1977N–0094L, unless                           13. Piper, J. M. et al, ‘‘Corticosteroid Use
                                               alcohol (see section VII.B of this                      otherwise indicated, and may be seen by               and Peptic Ulcer Disease: Role of
                                               document).                                              interested persons between 9 a.m. and 4               Nonsteroidal Anti-Inflammatory Drugs,’’
                                                  6. Both comment and data on whether                  p.m., Monday through Friday. (FDA has                 Annals of Internal Medicine, 114(9):735–740,
                                                                                                                                                             1991.
                                               combinations of acetaminophen with                      verified the Web site addresses, but we                  14. Wilcox, C. M. et al, ‘‘Striking
                                               NAC or methionine would prevent or                      are not responsible for subsequent                    Prevalence of Over-the-Counter Nonsteroidal
                                               reduce acetaminophen-induced liver                      changes to the Web sites after this                   Anti-Inflammatory Drug Use in Patients With
                                               toxicity (see section VII.C of this                     document publishes in the Federal                     Upper Gastrointestinal Hemorrhage,’’
                                               document).                                              Register.)                                            Archives of Internal Medicine, 154:42–46,
                                                  7. Both comment and data on package                     1. Comment No. C1, Docket No. 1977N–               1994.
                                               size or package configuration limitations               0094I (formerly Docket No. 77N–094I).                    15. Garcia-Rodriguez, L. A. and S.
                                               on the sale of acetaminophen (see                          2. Comment No. C2, Docket No. 1977N–               Hernandez-Diaz, ‘‘Relative Risk of Upper
                                               section VII.D of this document).                        0094I (formerly Docket No. 77N–094I).                 Gastrointestinal Complications Among Users
                                                                                                          3. FDA background information for                  of Acetaminophen and Nonsteroidal Anti-
                                                  8. Both comment and data on whether
                                                                                                       September 19–20, 2002, NDAC meeting,                  Inflammatory Drugs,’’ Epidemiology,
                                               acetaminophen poses additional risk for                 http://www.fda.gov/ohrms/dockets/ac/02/               12(5):570–576, 2001.
                                               certain population subgroups (e.g.,                     briefing/3882b1.htm.                                     16. Blot, W. J. and J. K. McLaughlin, ‘‘Over
                                               conditions in which GSH is reduced)                        4. NDAC meeting September 19–20, 2002              the Counter Non-steroidal Anti-Inflammatory
                                               (see section VII.E of this document).                   transcript, http://www.fda.gov/ohrms/                 Drugs and Risk of Gastrointestinal Bleeding,’’
                                                  9. Both comment and data on whether                  dockets/ac/02/transcripts/3882T1.htm. and             Journal of Epidemiology and Biostatistics,
                                               additional labeling is necessary                        http://www.fda.gov/ohrms/dockets/ac/02/               5(2):137–142, 2000.
                                               regarding acetaminophen-warfarin drug-                  transcripts/3882T2.htm.                                  17. Sorensen, H. T. et al., ‘‘Risk of Upper
                                               drug interaction (see section VII.F of                     5. Additional information submitted for            Gastrointestinal Bleeding Associated With
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                                               this document).
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                                                  10. Comment on the proposal to                          6. Lee, W. M., ‘‘Acute Liver Failure in the           18. Peura, D. A. et al., ‘‘The American
                                               include a warning on acetaminophen                      USA: Results of the US ALF Study Group,’’             College of Gastroenterology Bleeding
                                               products for patients with liver disease                September 19, 2002 NDAC meeting                       Registry: Preliminary Findings,’’ American
                                               to ask their doctor for advice. Also,                   transcript, http://www.fda.gov/ohrms/                 Journal of Gastroenterology, 92(6):924–928,
                                               request information and data on the                     dockets/ac/02/transcripts/3882T1.htm and              1997.
                                               current dosing practices of health                      slides http://www.fda.gov/ohrms/dockets/ac/              19. Kaufman, D. W. et al., ‘‘The Risk of
                                               providers who treat patients with                       02/slides/3882S1_04_Lee_files/frame.htm.              Acute Major Upper Gastrointestinal Bleeding
                                                                                                          7. Nourjah, P., S. A. Ahmad, and C. B.             Among Users of Aspirin and Ibuprofen at
mstockstill on PROD1PC61 with PROPOSALS




                                               underlying liver disease.
                                                  Interested persons may submit to the                 Karwoski, ‘‘ Safety Analysis of                       Various Levels of Alcohol Consumption,’’
                                                                                                       Acetaminophen A.P.A.P.-Associated                     American Journal of Gastroenterology,
                                               Division of Dockets Management (see                     Hepatotoxicity,’’ FDA Office of Drug Safety           94:3189–3196, 1999.
                                               ADDRESSES) written or electronic                        Analysis, September 19, 2002, NDAC                       20. Griffin, M., ‘‘NSAIDs and GI and Renal
                                               comments regarding this document.                       meeting transcript, http://www.fda.gov/               Complications,’’ presentation at September
                                               Submit a single copy of electronic                      ohrms/dockets/ac/02/transcripts/3882T1.htm            20, 2002, NDAC meeting, transcript http://
                                               comments or three hard copies of any                    and slides http://www.fda.gov/ohrms/                  www.fda.gov/ohrms/dockets/ac/02/



                                          VerDate Aug<31>2005   13:25 Dec 22, 2006   Jkt 211001   PO 00000   Frm 00037   Fmt 4702   Sfmt 4702   E:\FR\FM\26DEP1.SGM   26DEP1
                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                                77347

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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                          77349

                                               The Journal of the American Medical                     I 2. Section 201.66 is amended by                     cold) must include the name
                                               Association, 279(9): 702–703, 1998.                     revising paragraph (c)(5)(ii)(E) to read as           ‘‘acetaminophen’’ and the name(s) of the
                                                  122. Caraco, Y., J. Sheller, and A. J. Wood,         follows:                                              other active ingredient(s) in the product
                                               ‘‘Pharmacogenetic determination of the                                                                        on the PDP in accord with this
                                               effects of codeine and prediction of drug               § 201.66 Format and content requirements
                                               interactions,’’ Journal of Pharmacology and
                                                                                                                                                             paragraph. Only the name
                                                                                                       for over-the-counter (OTC) drug product
                                               Experimental Therapeutics, 278(3):1165–                 labeling.                                             ‘‘acetaminophen’’ must appear
                                               1174, 1996.                                                                                                   highlighted or in bold type, and in a
                                                                                                       *       *     *   *     *                             prominent print size, as described in
                                                  123. van den Bemt, P. M. et al., ‘‘The                  (c) * * *
                                               potential interaction between oral                         (5) * * *                                          this paragraph.
                                               anticoagulants and acetaminophen in                                                                              (iii) For products labeled for adults
                                                                                                          (ii) * * *
                                               everyday practice,’’ Pharmaceutical World                                                                     only. Warnings. The labeling of the
                                                                                                          (E) Liver warning set forth in
                                               Science, 24(5):201–204, 2002.                                                                                 product states the following warnings
                                                  124. Fattinger, K. et al., ‘‘No clinically           § 201.325(a)(1)(iii) and/or stomach
                                                                                                       bleeding warning set forth in                         under the heading ‘‘Warnings’’:
                                               relevant drug interaction between
                                               paracetamol and phenoprocoumon based on                 § 201.325(a)(2)(iii). The liver warning                  (A) ‘‘Liver warning [heading in bold
                                               a pharmacoepidemiological cohort study in               shall follow the subheading ‘‘Liver                   type]: This product contains
                                               medical in people,’’ European Journal of                warning:’’ and the stomach bleeding                   acetaminophen. Severe liver damage
                                               Clinical Pharmacology, 57(12): 863–867,                 warning shall follow the subheading                   may occur if you take [bullet] more than
                                               2002.                                                   ‘‘Stomach bleeding warning:’’                         [insert maximum number of daily
                                                  125. La Grenad, L., D. J. Graham, and P.                                                                   dosage units] in 24 hours [bullet] with
                                               Nourjah, ‘‘Underreporting of hemorrhagic                *       *     *   *     *
                                                                                                                                                             other drugs containing acetaminophen
                                               stroke associated with                                  § 201.322    [Removed]                                [bullet] 3 or more alcoholic drinks every
                                               phenylpropanolamine,’’ The Journal of the
                                               American Medical Association; 286: 3081,                  3. Section 201.322 is removed.                      day while using this product’’. This
                                               2001.                                                     4. Section 201.325 is added to subpart              ‘‘Liver warning’’ must be the first
                                                  126. Phelan, K., ‘‘OPDRA Postmarketing               G to read as follows:                                 warning under the ‘‘Warnings’’ heading.
                                               Safety Review: Acetaminophen and                                                                              For products that contain both
                                                                                                       § 201.325 Over-the-counter drug products
                                               Coumadin (drug interaction affecting                                                                          acetaminophen and aspirin, this ‘‘Liver
                                                                                                       containing internal analgesic/antipyretic
                                               anticoagulation),’’ FDA review dated April
                                                                                                       active ingredients; required warnings and             warning’’ must appear after the ‘‘Reye’s
                                               20, 2001.                                                                                                     syndrome’’ and ‘‘Allergy alert’’
                                                                                                       other labeling.
                                                  127. Karwoski, C. B., ‘‘Office of Drug Safety                                                              warnings in § 201.66(c)(5)(ii)(A) and
                                               Postmarketing Safety Review (DO30283)                      (a) Labeling. The labeling for all over-
                                                                                                       the-counter (OTC) drug products                       (c)(5)(ii)(B) and before the ‘‘Stomach
                                               Drugs—Acetaminophen and Warfarin,
                                               Reaction: Drug Interaction affecting                    containing any internal analgesic/                    bleeding warning’’ in paragraph
                                               Anticoagulation (update),’’ FDA review dated            antipyretic active ingredients                        (a)(2)(iii)(A) of this section.
                                               June 27, 2003.                                          (including, but not limited to,                          (B) ‘‘Do not use [heading in bold type]
                                                  128. Neuner, R., ‘‘Potentiation of                   acetaminophen, aspirin, carbaspirin                   with any other drug containing
                                               Anticoagulaton Status Due to a Possible                 calcium, choline salicylate, ibuprofen,               acetaminophen (prescription or
                                               Adverse Drug Interaction Between Warfarin                                                                     nonprescription). Ask a doctor or
                                                                                                       ketoprofen, magnesium salicylate,
                                               and Acetaminophen,’’ FDA review dated July                                                                    pharmacist before using with other
                                               9, 2003.                                                naproxen sodium, and sodium
                                                                                                       salicylate) alone or in combination must              drugs if you are not sure.’’
                                                  129. Eastern Research Group, Inc. ‘‘Cost                                                                      (C) ‘‘Ask a doctor before use if you
                                               Benefit Analysis of Proposed FDA Rule on                bear the following labeling in
                                               Over-the-Counter Internal Analgesic,                    accordance with §§ 201.60, 201.61, and                have [heading in bold type] liver
                                               Antipyretic, and Antirheumatic Drug                     201.66.                                               disease’’.
                                               Products; Required Warnings’’, Final Report,               (1) Acetaminophen.                                    (iv) For products labeled only for
                                               October 6, 2004.                                           (i) Principal display panel. The                   children under 12 years of age. (A)
                                                                                                       presence of ‘‘acetaminophen’’ in the                  Warnings. The labeling of the product
                                               List of Subjects                                                                                              states the following warnings under the
                                                                                                       product must be prominently stated on
                                               21 CFR Part 201                                         the principal display panel (PDP), as                 heading ‘‘Warnings’’:
                                                                                                       defined in § 201.60.                                     (1) ‘‘Liver warning [heading in bold
                                                 Drugs, Labeling, Reporting and                           (ii) Statement of identity. The                    type]: This product contains
                                               recordkeeping requirements.                             statement of identity appears in accord               acetaminophen. Severe liver damage
                                               21 CFR Part 343                                         with §§ 201.61, 299.4, and 343.50(a) of               may occur if the child takes [bullet]
                                                                                                       this chapter. The ingredient name                     more than 5 doses in 24 hours [bullet]
                                                 Labeling, Over-the-counter drugs.                     acetaminophen must appear highlighted                 with other drugs containing
                                                 Therefore, under the Federal Food,                    (e.g., fluorescent or color contrast) or in           acetaminophen’’. This ‘‘Liver warning’’
                                               Drug, and Cosmetic Act and under                        bold type, be in lines generally parallel             must be the first warning under the
                                               authority delegated to the Commissioner                 to the base on which the package rests                ‘‘Warnings’’ heading.
                                               of Food and Drugs, it is proposed that                  as it is designed to be displayed, and be                (2) ‘‘Do not use [heading in bold type]
                                               21 CFR parts 201 and 343 (as proposed                   in one of the following sizes, whichever              with any other drug containing
                                               in the Federal Register of November 16,                 is greater: (1) At least one-quarter as               acetaminophen (prescription or
                                               1988 and August 21, 2002) be amended                    large as the size of the most prominent               nonprescription). Ask a doctor or
                                               as follows:                                             printed matter on the PDP, or (2) at least            pharmacist before using with other
                                                                                                       as large as the size of the ‘‘Drug Facts’’            drugs if you are not sure.’’
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                                               PART 201—LABELING                                       title, as required in § 201.66(d)(2). The                (3) ‘‘Ask a doctor before use if the
                                                                                                       presence of acetaminophen must appear                 child has [heading in bold type] liver
                                                 1. The authority citation for 21 CFR                  as part of the established name of the                disease’’.
                                               part 201 continues to read as follows:                  drug, as defined in § 299.4 of this                      (B) Directions. The labeling of the
                                                 Authority: 21 U.S.C. 321, 331, 351, 352,              chapter. Combination products                         product contains the following
                                               353, 355, 358, 360, 360b, 360g–360s, 371,               containing acetaminophen and a                        information under the heading
                                               374, 379e; 42 U.S.C. 216, 241, 262, 264.                nonanalgesic ingredient(s) (e.g., cough-              ‘‘Directions’’: ‘‘this product does not


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                                               77350                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               contain directions or warnings for adult                ingredient and the word ‘‘(NSAID)’’                   takes other drugs containing an NSAID
                                               use’’ [in bold type].                                   need to appear highlighted or in bold                 (aspirin, ibuprofen, naproxen, or others)
                                                  (v) For products labeled for adults                  type, and in a prominent print size, as               [bullet] takes more or for a longer time
                                               and children under 12 years of age.                     described in this paragraph.                          than directed’’. The ‘‘Stomach bleeding
                                               Warnings. The labeling of the product                      (iii) For products labeled for adults              warning’’ must appear after the ‘‘Reye’s
                                               states all of the warnings in paragraphs                only. Warnings. The labeling of the                   syndrome’’ and ‘‘Allergy alert’’
                                               (a)(1)(iii)(A), (a)(1)(iii)(B), and                     product states the following warnings                 warnings in §§ 201.66(c)(5)(ii)(A) and
                                               (a)(1)(iii)(C) of this section with the                 under the heading ‘‘Warnings’’:                       (c)(5)(ii)(B).
                                               following modifications:                                   (A) ‘‘Stomach bleeding warning                        (2) ‘‘Ask a doctor before use if the
                                                  (A) The Liver warning states ‘‘Liver                 [heading in bold type]: This product                  child has [heading in bold type] [bullet]
                                               warning [heading in bold type]: This                    contains a nonsteroidal anti-                         stomach problems that last or come
                                               product contains acetaminophen.                         inflammatory drug (NSAID), which may                  back, such as heartburn, upset stomach,
                                               Severe liver damage may occur if                        cause stomach bleeding. The chance is                 or stomach pain [bullet] ulcers [bullet]
                                               [bullet] adult takes more than [insert                  higher if you [bullet] are age 60 or older            bleeding problems [bullet] not been
                                               maximum number of daily dosage units]                   [bullet] have had stomach ulcers or                   drinking fluids [bullet] lost a lot of fluid
                                               in 24 hours [ bullet] child takes more                  bleeding problems [bullet] take a blood               due to vomiting or diarrhea [bullet] high
                                               than 5 doses in 24 hours [bullet] taken                 thinning (anticoagulant) or steroid drug              blood pressure [bullet] heart or kidney
                                               with other drugs containing                             [bullet] take other drugs containing an               disease [bullet] taken a diuretic’’.
                                               acetaminophen [bullet] adult has 3 or                   NSAID [aspirin, ibuprofen, naproxen, or                  (3) ‘‘Ask a doctor or pharmacist before
                                               more alcoholic drinks everyday while                    others] [bullet] have 3 or more alcoholic             use if the child is [heading in bold type]
                                               using this product.’’                                   drinks every day while using this                     [bullet] taking any other drug containing
                                                  (B) ‘‘Ask a doctor before use if the                 product [bullet] take more or for a                   an NSAID (prescription or
                                               user [heading in bold type] has liver                   longer time than directed’’. This                     nonprescription) [bullet] taking a blood
                                               disease.’’                                              ‘‘Stomach bleeding warning’’ must                     thinning (anticoagulant) or steroid
                                                  (2) Nonsteroidal anti-inflammatory                   appear after the ‘‘Reye’s syndrome’’ and              drug’’.
                                               analgesic/antipyretic active                            ‘‘Allergy alert’’ warnings in                            (4) ‘‘Stop use and ask a doctor if
                                               ingredients—including, but not limited                  § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For          [heading in bold type] [bullet] the child
                                               to, aspirin, carbaspirin calcium, choline               products that contain both                            feels faint, vomits blood, or has bloody
                                               salicylate, ibuprofen, ketoprofen,                      acetaminophen and aspirin, the                        or black stools. These are signs of
                                               magnesium salicylate, naproxen                          acetaminophen ‘‘Liver warning’’ in                    stomach bleeding. [bullet] stomach pain
                                               sodium, and sodium salicylate.                          § 201.325(a)(1)(iii) must appear before               or upset gets worse or lasts’’.
                                                  (i) Principal display panel. The                     the ‘‘Stomach bleeding warning’’ in this                 (B) Directions. The labeling of the
                                               presence of an ‘‘NSAID’’ ingredient in                  paragraph.                                            product contains the following
                                               the product must be prominently stated                     (B) ‘‘Ask a doctor before use if you               information under the heading
                                               on the principal display panel (PDP), as                have [heading in bold type] [bullet]                  ‘‘Directions’’: ‘‘this product does not
                                               defined in § 201.60.                                    stomach problems that last or come                    contain directions or warnings for adult
                                                  (ii) Statement of identity. The                      back, such as heartburn, upset stomach,               use’’ [in bold type].
                                               statement of identity appears in accord                 or stomach pain [bullet] ulcers [bullet]                 (v) For products labeled for adults
                                               with §§ 201.61, 299.4, and 343.50(a) of                 bleeding problems [bullet] high blood                 and children under 12 years of age.
                                               this chapter. The name of the NSAID                     pressure [bullet] heart or kidney disease             Warnings. The labeling of the product
                                               ingredient and the word ‘‘(NSAID)’’                     [bullet] taken a diuretic [bullet] reached            states all of the warnings in paragraphs
                                               must appear highlighted (e.g.,                          age 60 or older’’.                                    (2)(iii)(A) through (2)(iii)(D) of this
                                               fluorescent or color contrast) or in bold                  (C) ‘‘Ask a doctor or pharmacist before            section with the following
                                               type, be in lines generally parallel to the             use if you are [heading in bold type]                 modifications:
                                               base on which the package rests as it is                [bullet] taking any other drug containing                (A) The Stomach bleeding warning
                                               designed to be displayed, and be in one                 an NSAID (prescription or                             states ‘‘Stomach bleeding warning
                                               of the following sizes, whichever is                    nonprescription) [bullet] taking a blood              [heading in bold type]: This product
                                               greater: At least one-quarter as large as               thinning (anticoagulant) or steroid                   contains a nonsteroidal anti-
                                               the size of the most prominent printed                  drug’’.                                               inflammatory drug (NSAID), which may
                                               matter on the PDP, or at least as large                    (D) ‘‘Stop use and ask a doctor if                 cause stomach bleeding. The chance is
                                               as the size of the ‘‘Drug Facts’’ title, as             [heading in bold type] [bullet] you feel              higher if the user [bullet] has had
                                               required in § 201.66(d)(2). The word                    faint, vomit blood, or have bloody or                 stomach ulcers or bleeding problems
                                               ‘‘(NSAID)’’ must appear as part of the                  black stools. These are signs of stomach              [bullet] takes a blood thinning
                                               established name of the drug, as defined                bleeding. [bullet] stomach pain or upset              (anticoagulant) or steroid drug [bullet]
                                               in § 299.4 of this chapter, or after the                gets worse or lasts’’.                                takes other drugs containing an NSAID
                                               general pharmacological (principal                         (iv) For products labeled only for                 [aspirin, ibuprofen, naproxen, or others]
                                               intended) action of the NSAID                           children under 12 years of age.                       [bullet] takes more or for a longer time
                                               ingredient. For example, either of the                  Warnings. (A) The labeling of the                     than directed [bullet] is age 60 or older
                                               following would be acceptable:                          product states the following warnings                 [bullet] has 3 or more alcoholic drinks
                                               Ibuprofen Tablets (NSAID) or Pain                       under the heading ‘‘Warnings’’:                       everyday while using this product’’. The
                                               reliever/ fever reducer (NSAID).                           (1) ‘‘Stomach bleeding warning                     ‘‘Stomach bleeding warning’’ must
                                               Combination products containing an                      [heading in bold type]: This product                  appear after the ‘‘Reye’s syndrome’’ and
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                                               NSAID and a nonanalgesic ingredient(s)                  contains a nonsteroidal anti-                         ‘‘Allergy alert’’ warnings in
                                               (e.g., cough-cold) must include the                     inflammatory drug (NSAID), which may                  §§ 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B).
                                               name of the NSAID ingredient and the                    cause stomach bleeding. The chance is                    (B) The labeling states ‘‘Ask a doctor
                                               word ‘‘(NSAID)’’ in accord with this                    higher if the child [bullet] has had                  before use if the user has [heading in
                                               paragraph, and the name(s) of the other                 stomach ulcers or bleeding problems                   bold type] [bullet] stomach problems
                                               active ingredient(s) in the product on                  [bullet] takes a blood thinning                       that last or come back, such as
                                               the PDP. Only the name of the NSAID                     (anticoagulant) or steroid drug [bullet]              heartburn, upset stomach, or stomach


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                                                                    Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules                                                    77351

                                               pain [bullet] ulcers [bullet] bleeding                  information included in paragraph (a) of                 (i) For products containing any
                                               problems [bullet] high blood pressure                   this section.                                         ingredient in § 343.10 (a) through (f) The
                                               [bullet] heart or kidney disease [bullet]                 (d) Regulatory action. Any drug                     labeling states ‘‘Stop use and ask a
                                               taken a diuretic [bullet] not been                      product subject to this section that is               doctor if [heading in bold type] [bullet]1
                                               drinking fluids [bullet] lost a lot of fluid            not labeled as required and that is                   pain gets worse or lasts more than 10
                                               due to vomiting or diarrhea [bullet]                    initially introduced or initially                     days [bullet] fever gets worse or lasts
                                               reached age 60 or older.’’                              delivered for introduction into interstate            more than 3 days [bullet] redness or
                                                  (C) The labeling states ‘‘Ask a doctor               commerce after [date 12 months after                  swelling is present [bullet] any new
                                               or pharmacist before use if the user is                 date of publication of the final rule in              symptoms appear’’.
                                               [heading in bold type] [bullet] taking                  the Federal Register] is misbranded                   *       *     *    *     *
                                               any other drug containing an NSAID                      under section 502 of the Federal Food,                   (iii) For products containing
                                               (prescription or nonprescription)                       Drug, and Cosmetic Act (the act) (21                  acetaminophen identified in § 343.10(a).
                                               [bullet] taking a blood thinning                        U.S.C. 352) and is subject to regulatory              The labeling states the warnings in
                                               (anticoagulant) or steroid drug’’.                      action. Any drug product for which the                § 201.325(a)(1)(iii)(A), (a)(1)(iii)(B), and
                                                  (D) The labeling states ‘‘Stop use and               labeling required in this section was                 (a)(1)(iii)(C) and the following statement
                                               ask a doctor if [heading in bold type]                  voluntarily implemented before the date               must follow the general warning
                                               [bullet] the user feels faint, vomits                   of publication of the final rule that is              identified in § 330.1(g) of this chapter:
                                               blood, or has bloody or black stools.                   initially introduced or initially                     ‘‘Prompt medical attention is critical for
                                               These are signs of stomach bleeding.                    delivered for introduction into interstate            adults as well as for children even if you
                                               [bullet] stomach pain or upset gets                     commerce after [date 18 months after                  do not notice any signs or symptoms.’’
                                               worse or lasts’’.                                       date of publication of the final rule in                 (iv) * * *
                                                  (vi) Active ingredient(s). The active                the Federal Register] and that is not                    (A) The labeling states the warning in
                                               ingredient(s) section of the product’s                  labeled as required is misbranded under               paragraph (c)(1)(v)(B) plus the bulleted
                                               labeling, as defined in § 201.66(c)(2),                 section 502 of the act and is subject to              statement ‘‘asthma’’.
                                               contains the term ‘‘(NSAID)*’’ after the                regulatory action.                                    *       *     *    *     *
                                               NSAID active ingredient with an                                                                                  (v) * * *
                                               asterisk statement at the end of the                    PART 343—INTERNAL ANALGESIC,
                                                                                                       ANTIPYRETIC, AND ANTIRHEUMATIC                           (A) The labeling states the warning in
                                               active ingredient(s) section that defines                                                                     paragraph (c)(1)(i) of this section plus
                                               the term ‘‘NSAID’’ and states ‘‘*                       DRUG PRODUCTS FOR OVER-THE-
                                                                                                       COUNTER HUMAN USE                                     ‘‘[bullet] you feel faint, vomit blood, or
                                               nonsteroidal anti-inflammatory drug.’’                                                                        have bloody or black stools. These are
                                                  (b) New warnings information                           4. The authority citation for 21 CFR                signs of stomach bleeding. [bullet]
                                               statement. The labeling of any drug                     part 343 continues to read as follows:                stomach pain or upset gets worse or
                                               product subject to this section that is                                                                       lasts [bullet] ringing in the ears or loss
                                                                                                         Authority: 21 U.S.C. 321, 351, 352, 353,
                                               initially introduced or initially                       355, 360, 371.                                        of hearing occurs’’.
                                               delivered for introduction into interstate                 5. Section 343.50, as proposed at 53                  (B) The labeling states ‘‘Ask a doctor
                                               commerce before the effective date and                  FR 46255, November 16, 1988, and 67                   before use if you have [heading in bold
                                               within 12 months after the effective date               FR 54158, August 21, 2002, is further                 type] [bullet] stomach problems that last
                                               of the final rule or if relabeled at any                amended by revising paragraphs                        or come back, such as heartburn, upset
                                               time before the effective date of the final             (c)(1)(i), (c)(1)(iii), (c)(1)(iv)(A),                stomach, or stomach pain [bullet] ulcers
                                               rule must bear on its principal display                 (c)(1)(v)(A) through (c)(1)(v)(C),                    [bullet] bleeding problems [bullet] high
                                               panel (PDP), as defined in § 201.60, the                (c)(1)(ix)(A), (c)(1)(ix)(B), (c)(1)(ix)(C),          blood pressure [bullet] heart or kidney
                                               statement ‘‘See new warnings                            (c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii),                disease [bullet] taken a diuretic [bullet]
                                               information.’’ This statement must                      (c)(2)(iv)(A), (c)(2)(v)(A) through                   reached age 60 or older’’.
                                               appear highlighted (e.g., fluorescent or                (c)(2)(v)(C)3 and adding new paragraphs                  (C) The labeling states ‘‘Ask a doctor
                                               color contrast) or in bold type, be in                  (b)(4)(i)(C) and (c)(3)(i) through                    or pharmacist before use if you are
                                               lines generally parallel to the base on                 (c)(3)(v)(C) to read as follows:                      [heading in bold type] [bullet] taking
                                               which the package rests as it is designed                                                                     any other drug containing an NSAID
                                               to be displayed, and be in one of the                   § 343.50 Labeling of analgesic-antipyretic            (prescription or nonprescription)
                                               following sizes, whichever is greater:                  drug products.                                        [bullet] taking a blood thinning
                                                  (1) At least one-quarter as large as the             *      *     *      *    *                            (anticoagulant) or steroid drug [bullet]
                                               size of the most prominent printed                         (b) * * *                                          taking a prescription drug for diabetes,
                                               matter on the PDP, or                                      (4) * * *                                          gout, or arthritis’’.
                                                  (2) At least as large as the size of the                (i) * * *
                                                                                                                                                             *       *     *    *     *
                                               ‘‘Drug Facts’’ title, as required in                       (C) The product states the following
                                                                                                                                                                (ix) * * *
                                               § 201.66(d)(2).                                         statement under the heading
                                                                                                                                                                (A) The stomach bleeding warning set
                                                  (c) Requirements to supplement                       ‘‘Directions,’’ ‘‘this product does not
                                                                                                                                                             forth in § 201.325(a)(2)(iii)(A),
                                               approved application. Holders of                        contain directions or warnings for adult
                                                                                                                                                             (a)(2)(iv)(A), or (a)(2)(v)(A) of this
                                               approved applications for OTC drug                      use’’. This statement is not required for
                                                                                                                                                             chapter appears after the subheading
                                               products that contain internal analgesic/               products containing ibuprofen as
                                                                                                                                                             ‘‘Stomach bleeding warning:’’.
                                               antipyretic active ingredients that are                 identified in § 343.10 (g).
                                                                                                                                                                (B) The labeling states ‘‘Ask a doctor
                                               subject to the requirements of paragraph                *      *     *      *    *                            before use if you have [heading in bold
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                                               (a) of this section must submit                            (c) * * *                                          type] [bullet] problems or serious side
                                               supplements under § 314.70(c) of this                      (1) * * *                                          effects from taking pain relievers or
                                               chapter to include the required                                                                               fever reducers [bullet] stomach
                                                                                                          3The warnings in these sections are revised to
                                               information in the product’s labeling.                                                                        problems that last or come back, such as
                                                                                                       conform with § 201.66 (Drug Facts format). Other
                                               Such labeling may be put into use                       warnings remain as proposed in the TFM and will
                                               without advance approval of FDA                         be revised into the Drug Facts format in a future       1See § 201.66(b)(4) of this chapter for definition

                                               provided it includes at least the exact                 issue of the Federal Register.                        of bullet symbol.



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                                               77352                Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules

                                               heartburn, upset stomach, or stomach                    bold type] [bullet] stomach problems                  taking a prescription drug for diabetes,
                                               pain [bullet] ulcers [bullet] bleeding                  that last or come back, such as                       gout, or arthritis’’.
                                               problems [bullet] high blood pressure                   heartburn, upset stomach, or stomach                    Dated: November 22, 2006.
                                               [bullet] heart or kidney disease [bullet]               pain [bullet] ulcers [bullet] bleeding
                                               taken a diuretic [bullet] reached age 60                problems [bullet] not been drinking                   Jeffrey Shuren,
                                               or older’’.                                             fluids [bullet] lost a lot of fluid due to            Assistant Commissioner for Policy.
                                                  (C) The labeling states ‘‘Ask a doctor               vomiting or diarrhea [bullet] high blood              [FR Doc. E6–21855 Filed 12–19–06; 8:45 am]
                                               or pharmacist before use if you are                     pressure [bullet] heart or kidney disease             BILLING CODE 4160–01–S
                                               [heading in bold type] [bullet] taking                  [bullet] taken a diuretic’’.
                                               any other drug containing an NSAID                         (C) The labeling states ‘‘Ask a doctor
                                               (prescription or nonprescription [bullet]               or pharmacist before use if the child is
                                               taking a blood thinning (anticoagulant)                 [heading in bold type] [bullet] taking                DEPARTMENT OF THE TREASURY
                                               or steroid drug [bullet] under a doctor’s               any other drug containing an NSAID
                                               care for any serious condition [bullet]                 (prescription or nonprescription)                     Internal Revenue Service
                                               taking any other drug’’.                                [bullet] taking a blood thinning
                                               *       *     *    *     *                              (anticoagulant) or steroid drug [bullet]              26 CFR Part 1
                                                  (E) In addition to the warning                       taking a prescription drug for diabetes,
                                               required in § 201.324(c) of this chapter                gout, or arthritis’’.                                 [REG–136806–06]
                                               after the subheading ‘‘Stop use and ask                 *       *     *    *     *
                                               a doctor if’’ [heading in bold type], the                  (3) * * *                                          RIN 1545–BF87
                                               following statements also appear:                          (i) For products containing any
                                               ‘‘[bullet] you feel faint, vomit blood, or              ingredient in § 343.10 (a) through (f).               Treatment of Payments in Lieu of
                                               have bloody or black stools. These are                  The labeling states ‘‘Stop use and ask a              Taxes Under Section 141
                                               signs of stomach bleeding. [bullet] pain                doctor if [heading in bold type] [bullet]
                                               gets worse or lasts more than 10 days                   adult’s pain gets worse or lasts more                 AGENCY: Internal Revenue Service (IRS),
                                               [bullet] fever gets worse or lasts more                 than 10 days [bullet] child’s pain gets               Treasury.
                                               than 3 days [bullet] stomach pain or                    worse or lasts more than 5 days [bullet]
                                               upset gets worse or lasts [bullet] redness              fever gets worse or lasts more than 3                 ACTION: Change of location of public
                                               or swelling is present in the painful area              days [bullet] redness or swelling is                  hearing.
                                               [bullet] any new symptoms appear‘‘.                     present [bullet] any new symptoms
                                               *       *     *    *     *                              appear’’.                                             SUMMARY: On October 19, 2006, on page
                                                  (2) * * *                                               (ii) The warning in § 343.50(c)(1)(ii), if         61693 of the Federal Register (71 FR
                                                  (i) For products containing any                      applicable.                                           61693), a notice of proposed rulemaking
                                               ingredient in § 343.10 (a) through (f) The                 (iii) For products containing                      and notice of public hearing announced
                                               labeling states ‘‘Stop use and ask a                    acetaminophen identified in § 343.10(a).              that a public hearing concerning
                                               doctor if [heading in bold type] [bullet]               The labeling states the warnings in                   applying the private security or
                                               pain gets worse or lasts more than 5                    § 201.325(a)(1)(v) of this chapter. The               payment test for State and local
                                               days [bullet] fever gets worse or lasts                 warning in § 201.325 (a)(1)(v)(B) is                  governmental issuers of tax-exempt
                                               more than 3 days [bullet] redness or                    modified to read: ‘‘ Ask a doctor before              bonds will be held February 13, 2007 in
                                               swelling is present [bullet] any new                    use if the user [heading in bold type]                the auditorium of the New Carrollton
                                               symptoms appear ’’.                                     [bullet] has liver disease [bullet] is a              Federal Building, 5000 Ellin Road,
                                               *       *     *    *     *                              child with pain of arthritis’’. The                   Lanham, MD 20706. The location of the
                                                  (iii) For products containing                        following statement must follow the                   public hearing has changed.
                                               acetaminophen identified in § 343.10(a).                general warning identified in § 330.1(g)
                                               The labeling states the warnings in                     of this chapter: ‘‘Prompt medical                     ADDRESSES:   The public hearing will be
                                               § 201.325(a)(1)(iv)(A)(1), (a)(1)(iv)(A)(2),            attention is critical for adults as well as           held in the IRS Auditorium, Internal
                                               and (a)(1)(iv)(A)(3) and the following                  for children even if you do not notice                Revenue Building, 1111 Constitution
                                               statement must follow the general                       any signs or symptoms.’’                              Avenue, NW., Washington, DC.
                                               warning identified in § 330.1(g) of this                   (iv) The warnings in § 343.50(c)(1)(iv),
                                                                                                                                                             FOR FURTHER INFORMATION CONTACT:
                                               chapter: ‘‘Prompt medical attention is                  if applicable.
                                                                                                                                                             Concerning submissions of comments,
                                               critical even if you do not notice any                     (v) For products containing aspirin,
                                                                                                       carbaspirin calcium, choline salicylate,              the hearing, and/or to be placed on the
                                               signs or symptoms.’’
                                                  (iv) * * *                                           magnesium salicylate, or sodium                       building access list to attend the hearing
                                                  (A) The labeling states the warning in               salicylate identified in §§ 343.10(b), (c),           Kelly Banks, (202) 622–0392 (not a toll-
                                               paragraph (c)(2)(v)(B) plus the bulleted                (d), (e) and ( f).                                    free number).
                                               statement ‘‘asthma’’.                                      (A) The labeling states the warning in             LaNita Van Dyke,
                                               *       *     *    *     *                              paragraph (c)(3)(i) of this section plus              Branch Chief, Publications and Regulations,
                                                  (v) * * *                                            ‘‘[bullet] the user feels faint, vomits               Associate Chief Counsel, Legal Processing
                                                  (A) The labeling states the warning in               blood, or has bloody or black stools.                 Division, (Procedure and Administration).
                                               paragraph (c)(2)(i) of this section plus                These are signs of stomach bleeding.                  [FR Doc. E6–22017 Filed 12–22–06; 8:45 am]
                                               ‘‘[bullet] the child feels faint, vomits                [bullet] stomach pain or upset gets
mstockstill on PROD1PC61 with PROPOSALS




                                                                                                                                                             BILLING CODE 4830–01–P
                                               blood, or has bloody or black stools.                   worse or lasts [bullet] ringing in the ears
                                               These are signs of stomach bleeding.                    or loss of hearing occurs’’.
                                               [bullet] stomach pain or upset gets                        (B) The labeling states the warning in
                                               worse or lasts [bullet] ringing in the ears             § 201.325(a)(2)(v)(B) plus ‘‘[bullet] is a
                                               or loss of hearing occurs’’.                            child with pain of arthritis’’.
                                                  (B) The labeling states ‘‘Ask a doctor                  (C) The labeling states the warning in
                                               before use if the child has [heading in                 § 201.325(a)(2)(v)(C) plus ‘‘[bullet]


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