Revising ANDA 
Labeling Following 
Revision of the RLD 
Labeling 
Guidance for Industry 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2024 
Generic Drugs 
  Contains Nonbinding Recommendations 
 
 
Revising ANDA 
Labeling Following 
Revision of the RLD 
Labeling 
Guidance for Industry 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2024 
Generic Drugs 
 
 
 
 
 
 
 
 
 
 
 
 
i  Contains Nonbinding Recommendations 
 
 TABLE OF CONTENTS 
 
   
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  HOW TO OBTAIN INFORMATION ON CHANGES TO RLD LABELING .......... 4 
IV.  HOW TO SUBMIT REVISED LABELING .................................................................. 4 
A.  Process ............................................................................................................................................. 4 
B.  Type of Submission ........................................................................................................................ 5 
1. Unapproved ANDAs......................................................................................................................... 5 
2. Tentatively Approved ANDAs .......................................................................................................... 6 
3. Approved ANDAs ............................................................................................................................. 6 
C.  Other Considerations ..................................................................................................................... 6 
ii  Contains Nonbinding Recommendations 
 
Revising ANDA Labeling Following Revision of the RLD Labeling 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist applicants and holders of an abbreviated new drug 
application (ANDA) in updating their labeling following revisions to the approved labeling2 of 
a reference listed drug (RLD).3,4  This guidance provides recommendations on identifying 
RLD labeling updates and submitting ANDA amendments or supplements to update 
generic drug labeling.  This guidance finalizes the draft guidance for industry of the same 
title issued on January 27, 2022.5 The final guidance provides clear expectations for when 
updates to labeling are required, the process for updating labeling, and the types of 
submissions for labeling updates. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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. 
 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration. 
2 In this guidance, we use the terms approved labeling or labeling to refer to labeling approved in New Drug 
Applications (NDAs) and ANDAs.  This term includes but is not limited to:  Prescribing Information (PI), FDA-
approved patient labeling (Medication Guides, Instructions for Use, and Patient Information (also called Patient 
Package Inserts)), and carton and container labeling.  
 
3 This guidance encompasses approved labeling for prescription and certain over the counter (OTC) drugs.  For 
more information and resources on prescription drug labeling, please visit https://www.fda.gov/drugs/laws-acts-and-
rules/prescription-drug-labeling-resources.  For OTC products, please refer to the FDA guidance for industry 
Labeling OTC Human Drug Products Updating Labeling in RLDs and ANDAs (October 2002). 
 
4 An RLD is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking 
approval of its ANDA (21 CFR 314.3(b)). 
 
5 We update guidances periodically.  For the most recent version of a guidance, check  
the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents#guidancesearch. 
 
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
An ANDA is an application submitted and approved under section 505(j) of the Federal Food, 
Drug, and Cosmetic Act (FD&C Act)6  for a drug product that is a duplicate7 of a previously 
approved drug product.  An ANDA relies on FDAs finding that the previously approved drug 
producti.e., the RLDis safe and effective.  An ANDA generally must contain information to 
show that the proposed generic product: (1) is the same as the RLD with respect to the active 
ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling 
(with certain permissible differences); and (2) is bioequivalent to the RLD.8   
 
A generic drug is generally required to have the same labeling as the RLD, except for changes 
required because of differences approved under a suitability petition9 or because the generic drug 
and the RLD are produced or distributed by different manufacturers.10  FDA regulations 
provide examples of permissible differences in labeling that may result when a proposed generic 
drug and the RLD are produced or distributed by different manufacturers, including the 
omission of an indication or other aspect of labeling protected by patent or exclusivity and 
labeling revisions made to comply with current FDA labeling guidelines or other guidance.11  
FDA will refuse to approve an ANDA if information submitted in the ANDA is insufficient to 
show that the labeling proposed for the generic drug is the same as the labeling approved for the 
RLD, except for changes required because of differences approved in a suitability petition; or 
because the proposed generic drug and the RLD are produced or distributed by different 
manufacturers; or because aspects of the RLDs labeling are protected by patent or exclusivity, 
and such differences do not render the proposed drug product less safe or effective than the RLD 
for all remaining, nonprotected conditions of use.12 
 
As a general matter, all holders of marketing applications for drug products (both new drug 
applications (NDAs) and ANDAs) have an ongoing obligation to ensure their product labeling is 
accurate and not false or misleading.  When new information becomes available that causes the 
labeling to become inaccurate, false, or misleading, the application holder must take steps to 
 
6 See 21 U.S.C. 355(j). 
 
7 The term duplicate generally refers to a drug product that has the same active ingredient(s), dosage form, strength, 
route of administration, and conditions of use as a listed drug.  See e.g., 54 FR 28872 at 28877 (July 10, 1989).  
However, the term duplicate, as used in this context, does not mean identical in all aspects to the listed drug.  These 
products are typically referred to as generic drugs. 
 
8 See e.g., sections 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see also e.g., 21 CFR  314.94(a) and  
314.127(a). 
 
9 See section 505(j)(2)(C) of the FD&C Act and 21 CFR  314.93. 
 
10 See section 505(j)(2)(A)(v) and (j)(4)(G) of the FD&C Act and 21 CFR  314.94(a)(8)(iv) and  314.127(a)(7). 
 
11 See  314.94(a)(8)(iv). 
 
12  314.127(a)(7). 
 
  2  Contains Nonbinding Recommendations 
 
update its labeling.13  A drug is misbranded if its labeling is false or misleading or does not 
provide adequate directions for use and adequate warnings.14 
 
Approved RLD labeling is revised by its application holder for a variety of reasons and is 
accomplished through the submission of information to the application under the appropriate 
reporting category.15  An ANDA holder is expected to update its labeling after FDA has approved 
relevant changes to the labeling for the corresponding RLD.  Prompt revision, submission to the 
Agency, and implementation of revised ANDA labeling are important to ensure that the generic 
drug continues to be as safe and effective as the corresponding RLD.  FDA may withdraw 
approval of an ANDA if the Agency finds that the labeling for the drug product that is the 
subject of the ANDA is no longer consistent with that for the RLD.16  FDA recommends that 
ANDA holders and applicants submit revised ANDA labeling at the earliest time possible 
because the labeling of a generic drug generally must be the same as that of the RLD (with 
certain permissible differences).17  It is the ANDA holder or applicants 
 
13 See, e.g., 21 CFR  201.56(a)(2). 
 
14 See sections 301(a) and (b) and 502(a), (f), and (j) of the FD&C Act (21 U.S.C. 331(a) and (b) and 352(a), (f), and 
(j)). 
 
15 See 21 CFR  314.70 and 21 CFR  314.71; additional recommendations are contained in FDA guidances for 
industry Changes to an Approved NDA or ANDA (April 2004, Rev. 1) and ANDA Submissions  Prior Approval 
Supplements Under GDUFA (October 2022, Rev. 2). 
 
16 See section 505(e) of the FD&C Act and 21 CFR  314.150(b)(10). 
 
17 See e.g., footnotes 9 and 15.  There may be circumstances in which an ANDA holder updates its labeling, even 
though there has not been an update to the labeling for the corresponding RLD.  For example, an ANDA holder for a 
product that omits an indication included in the NDA RLD labeling because of patent or exclusivity protection 
updates the product labeling to include that indication upon expiration of the patent or exclusivity.  See section 
505(j)(2)(A)(v) of the FD&C Act and  314.94(a)(8)(iv).  Another example is that if an ANDA applicant makes 
certain other changes to its product that are permissible, such as changes to a container closure system, then it can 
update the product labeling accordingly.  For more information, please see the FDA guidance for industry ANDA 
Submissions  Prior Approval Supplements Under GDUFA (October 2022, Rev. 2) and the draft guidance for 
industry Postapproval Changes to Drug Substances (September 2018).  When final, this guidance will represent the 
FDAs current thinking on this topic.  We update guidances periodically.  For the most recent version of a guidance, 
check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents).   
 
If approval of the RLDs application has been withdrawn for reasons other than safety or effectiveness, the labeling 
of a pending or marketed ANDA product may need to be updated.  The Consolidated Appropriations Act, 2021 
(Pub. L.  116-133 (Dec. 2020)), contains provisions that added new section 503D to the FD&C Act (codified at 21 
U.S.C. 353d).  Section 503D provides a process to update labeling for certain generic drugs that reference an RLD 
where the approval of the RLD has been withdrawn for reasons other than safety or effectiveness.  FDA also has 
draft guidance on this topic, but this draft guidance does not address the process for updating labeling under section 
503D of the FD&C Act because it was issued prior to the enactment of section 503D (see draft guidance for industry 
Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn (July 
2016)).  When final, this guidance will represent the FDAs current thinking on this topic.  Updating ANDA labeling 
when the RLD has been withdrawn for reasons other than safety or effectiveness is outside the scope of this 
guidance and applicants should refer to section 503D of the FD&C Act or the draft guidance for industry guidance 
and applicants should refer to section 503D of the FD&C Act or the draft guidance for industry Updating ANDA 
Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn, as appropriate. 
 
 
  3  Contains Nonbinding Recommendations 
 
 
responsibility to monitor for RLD labeling changes and to submit revised ANDA labeling to 
FDA in a timely fashion. 
 
 
III.  HOW TO OBTAIN INFORMATION ON CHANGES TO RLD LABELING 
 
ANDA applicants and holders should routinely monitor Drugs@FDA for recently approved 
RLD labeling updates and make any necessary revisions to their labeling.  The web page for 
Drugs@FDA is https://www.accessdata.fda.gov/scripts/cder/daf/. 
 
In addition, FDA maintains LISTSERVs that provide information about new approvals and 
announcements related to labeling updates.  For email updates, subscribe to CDER Drug Safety 
Labeling Changes and CDER New at https://www.fda.gov/about-fda/contact-fda/get-email-
updates. 
 
All approved RLD labeling is available from FDAs Division of Freedom of Information.  
Applicants who wish to obtain labeling using this mechanism should send a written request 
via mail, fax, or the internet to: 
 
Food and Drug Administration  
Division of Freedom of Information 
Office of the Executive Secretariat, OC 
5630 Fishers Lane, Room 1035 
Rockville, MD 20857 
 
301-796-3900 (phone); 301-827-9267 (fax) 
http://www.accessdata.fda.gov/scripts/foi/FOIRequest/index.cfm 
 
 
IV.  HOW TO SUBMIT REVISED LABELING 
 
A.  Process   
 
Consistent with the statute,18 labeling changes for an ANDA must be submitted in 
electronic format through the Electronic Submissions Gateway19 as described in the FDA 
guidance for industry Providing Regulatory Submissions in Electronic Format  Certain 
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD 
Specifications (February 2020, Rev. 7).20  Note that certain types of submissions (e.g., for 
 
 
18 See 21 U.S.C. 379k-1. 
 
19 See the Electronic Submissions Gateway web page at https://www.fda.gov/industry/electronic-submissions-
gateway for technical details related to submitting documents through FDAs Electronic Submissions Gateway. 
 
20 For more information, please visit www.fda.gov/eCTD.  
 
  4  Contains Nonbinding Recommendations 
 
certain positron emission tomography drugs) may be exempted from the Electronic Common 
Technical Document (eCTD) requirements.21  
  
ANDA applicants and holders should submit the respective labeling documents in the 
appropriate modules and sections according to the Comprehensive Table of Contents 
Headings and Hierarchy located at FDAs eCTD web page.22 
 
Such submissions should include: 
 
  Form FDA 356h23 
  Cover letter24 
  Patent and exclusivity statement in cover letter and/or eCTD submission, as needed 
  Revised labeling 
  A side-by-side comparison of the proposed ANDA labeling with the approved labeling 
of the RLD with all differences annotated and explained, as described in 
 314.94(a)(8)(iv) 
 
B.  Type of Submission 
 
ANDA applicants and holders should note that, in general, the submission of an unsolicited 
labeling amendment during a review cycle may impact the goal date.25  In certain limited 
circumstances, an applicant may submit revised labeling corresponding to an RLD labeling 
update after approval of the ANDA.26 
 
1.  Unapproved ANDAs 
 
For unapproved ANDAs, applicants should submit labeling changes to conform to RLD labeling 
updates in an amendment, following the procedures outlined in 21 CFR 314.96 and 
 
21 See page 6 of the FDA guidance for industry Providing Regulatory Submissions in Electronic Format  
Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications 
(February 2020, Rev. 7). 
 
22 See the current version of the Comprehensive Table of Contents Headings and Hierarchy in eCTD Submission 
Standards at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-
technical-document-ectd.  
 
23 Available on FDAs Forms website at:  https://www.fda.gov/about-fda/reports-manuals-forms/forms 
 
24 See FDAs guidance for industry Cover Letter Attachments for Controlled Correspondence and ANDA 
Submissions (June 2023). 
 
25 For more information on the timing of amendments and goal dates, see the FDA guidance for industry ANDA 
Submissions  Amendments to Abbreviated New Drug Applications Under GDUFA (July 2018). 
 
26 See section 505(j)(10) of the FD&C Act and MAPP 5230.3, Rev. 1, Generic Drug Labeling Revisions Covered 
Under Section 505(j)(10) of the Federal Food, Drug, and Cosmetic Act, at https://www.fda.gov/about-fda/center-
drug-evaluation-and-research-cder/cder-manual-policies-procedures-mapp. 
 
  5  Contains Nonbinding Recommendations 
 
recommendations in the FDA guidance for industry ANDA Submissions  Amendments to 
Abbreviated New Drug Applications Under GDUFA (July 2018).   
 
2.  Tentatively Approved ANDAs 
 
Similarly, for tentatively approved ANDAs, an applicant should submit labeling changes to 
conform to RLD labeling updates in an amendment to the tentatively approved application.  For 
recommendations on the timing and content of amendments to tentatively approved ANDAs to 
facilitate submission in a timely fashion and enable final approval on the earliest date on which 
the ANDA may lawfully be approved based on patent and/or exclusivity protections, refer to the 
FDA guidance for industry ANDA Submissions  Amendments and Requests for Final Approval 
to Tentatively Approved ANDAs (September 2020).   
 
3.  Approved ANDAs 
 
For approved ANDAs, ANDA holders generally must submit labeling updates to their ANDAs 
to conform to RLD labeling updates,27 using the appropriate reporting category as outlined in 
section 314.70.28  Additional recommendations can be found in the FDA guidances for industry 
Changes to an Approved NDA or ANDA (April 2004, Rev. 1) and ANDA Submissions  Prior 
Approval Supplements Under GDUFA (October 2022, Rev. 2). 
 
C.  Other Considerations 
 
ANDA applicants and holders should consider all aspects of labeling when submitting an update 
to ensure their submissions conform to the updates made to the labeling of the RLD.  For 
instance, when updating labeling for a particular section (e.g., WARNINGS AND 
PRECAUTIONS), ANDA applicants and holders should consider whether conforming updates 
to other sections of the labeling (e.g., DOSAGE AND ADMINISTRATION) are necessary 
because of updates made to the labeling of the RLD. 
 
 
  
 
 
 
 
  
 
27 As noted above in section II, certain differences in labeling may be permissible. 
 
28 See 21 CFR 314.97 (referencing 314.70 and 314.71). 
  6