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Guidance for Industry: Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use — Labeling

DRAFT GUIDANCE

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This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact Tina Walther at 301-796-5086.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)


July 2012
Compliance

Additional copies are available from:

Office of Communications
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 51, rm. 2201
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
Druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm


U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)


July 2012

Compliance

TABLE OF CONTENTS


I. INTRODUCTION


II.BACKGROUND

III. DISCUSSION AND POLICY

 

Guidance for Industry

Organ-Specific Warnings:  Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use —
Labeling for Products That Contain Acetaminophen

This draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You may use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

 

 

I.   Introduction

 

This draft guidance informs manufacturers of over-the-counter (OTC) internal analgesic, antipyretic, and antirheumatic (IAAA) drug products that contain acetaminophen of the circumstances in which FDA intends to exercise enforcement discretion with regard to the liver warning required under § 201.326(a)(1)(iii)(A) (21 CFR 201.326(a)(1)(iii)(A)).    

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidance documents describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

 

II.        Background

 

In the Federal Register of December 26, 2006 (71 FR 77314), FDA published a proposed rule on organ-specific warnings and related labeling for OTC IAAA drug products.  In the Federal Register of April 29, 2009 (74 FR 19385), FDA published the final rule (2009 final rule).  On November 25, 2009, FDA published a technical amendment (74 FR 61512) to clarify several provisions in response to industry feedback.  The 2009 final rule, as amended, changed various labeling requirements for OTC IAAA drug products to inform consumers about the risk of liver injury when using acetaminophen, and the risk of stomach bleeding when using nonsteroidal anti-inflammatory drugs.  It went into effect on April 29, 2010, and is codified at 21 CFR 201.326. 

Section 201.326(a)(1)(iii)(A) requires that the labeling for OTC IAAA products that contain acetaminophen and are labeled for adults only include the following liver warning:

Liver warning:  This product contains acetaminophen.  Severe liver damage may occur if you take  ● More than [insert maximum number of daily dosage units] in 24 hours, which is the maximum daily amount [optional: “for this product”] ● With other drugs containing acetaminophen  ●  3 or more alcoholic drinks every day while using this product.

Although the currently proposed maximum daily dose of acetaminophen is 4,000 milligrams (mg), some OTC products that contain acetaminophen have directions for use that provide a maximum daily dose of acetaminophen that is less than 4,000 mg for that product.  Directions for use can result in a maximum daily dose of acetaminophen that is less than 4,000 mg for a variety of reasons, including additional active ingredient(s) in the drug product, and administration and dosage limitations based upon specific product indications and intended uses.  In other instances, the limit on the daily dose of acetaminophen can be the result of a voluntary limitation by the manufacturer.  For example, the maximum number of daily dosage units for an OTC acetaminophen-diphenhydramine combination drug intended as nighttime sleep aid and internal analgesic product is limited by the product’s indication, and the total daily dose of acetaminophen for the product is significantly less than 4,000 mg.  The optional statement, “for this product,” in the first bullet of § 201.326(a)(1)(iii)(A) is intended to provide language to help consumers understand that the maximum number of daily dosage units for a product might not reflect the maximum daily dose of acetaminophen.   However, the Agency understands that in certain circumstances, despite this optional statement, the wording of the first bulleted warning required under § 201.326(a)(1)(iii)(A) might be interpreted as indicating that severe liver damage is associated with a total daily dose of acetaminophen that is less than 4,000 mg.  This suggestion is not intended by the regulation.

To address this potential confusion for OTC acetaminophen-containing products with directions for use that result in a maximum daily dose of less than 4,000 mg of acetaminophen, the Agency intends to exercise enforcement discretion in the circumstances described in section III.A below.  

 

III.      Discussion and Policy


 

A.        Products Labeled for Adults Only

 

When an OTC IAAA product containing acetaminophen is labeled for adults only and its directions for use result in a maximum daily dose of acetaminophen for the product that is less than 4,000 mg, FDA intends to exercise enforcement discretion if a manufacturer chooses to use the following language on the drug’s labeling, in place of the liver warning required by § 201.326(a)(1)(iii)(A):

Liver warning:  This product contains acetaminophen. Severe liver damage may occur if you take: ● More than 4,000 mg of acetaminophen in 24 hours ● With other drugs containing acetaminophen ● 3 or more alcoholic drinks every day while using this product.

FDA believes that this alternative language should eliminate the potential confusion described above and help ensure appropriate dosing of OTC acetaminophen-containing products, while also informing consumers that using more than the currently proposed maximum daily dose of 4,000 mg of acetaminophen may result in severe liver damage. 

 

B.        Products That Are Not Labeled for Adults Only

 

OTC IAAA products containing acetaminophen that are labeled only for children under 12 years of age, or for both adults and children under 12 years of age, must include in their labeling the liver warnings required under § 201.326(a)(1)(iv) and (v), respectively.  For acetaminophen products labeled only for use by children under 12 years of age, the required liver warning explicitly states that severe liver damage may occur if a child takes more than 5 doses in 24 hours, rather than more than the maximum number of daily dosage units for the particular product.  For acetaminophen products labeled for use by both adults and children under 12 years of age, the required liver warning allows for different maximum daily doses based on age.  For these products, FDA believes that the language described in section III.A. above would likely add to consumer confusion about appropriate dosing.  Therefore, FDA is not describing any general circumstances in which it intends to exercise enforcement discretion with respect to the liver warnings required for OTC IAAA acetaminophen products that are not labeled for adults only.

 

1.This draft guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
  

2.The Tentative Final Monograph for Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for OTC Human Use currently proposes that an OTC IAAA product with a daily dose of acetaminophen that does not exceed 4,000 milligrams (mg) in 24 hours, among other things, be considered generally recognized as safe and effective and not misbranded (see 53 FR 46204 at 46257 (November 16, 1988)).