Labeling for Biosimilar 
Products 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
July 2018 
Labeling 
 
 
 
   
Labeling for Biosimilar 
Products 
 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information, 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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email:  ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2018 
Labeling 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED 
BIOSIMILAR PRODUCTS (BIOSIMILAR PRODUCT LABELING) ................................. 3 
IV.  SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR PRODUCT 
LABELING ................................................................................................................................... 5 
A.  Approaches to Product Identification .......................................................................................... 5 
B.  Approaches to Content Presentation............................................................................................ 7 
C.  Approaches to Specific Sections of Biosimilar Product Labeling .............................................. 8 
V.  FDA-APPROVED PATIENT LABELING .................................................................. 10 
VI.  REVISING BIOSIMILAR PRODUCT LABELING .................................................. 10 
A.  Updating Safety Information ...................................................................................................... 10 
B.  Additional Conditions of Use ...................................................................................................... 11 
VII.  HOW TO SUBMIT INITIAL AND REVISED LABELING ..................................... 11 
VIII.  INTERCHANGEABLE PRODUCTS .......................................................................... 12 
  Contains Nonbinding Recommendations 
 
 
Labeling for Biosimilar Products 
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 help applicants develop draft labeling for proposed biosimilar 
products for submission in an application under section 351(k) of the Public Health Service Act 
(PHS Act) (42 U.S.C. 262(k)).  The recommendations for prescription drug labeling in this 
guidance pertain only to the prescribing information (commonly referred to as the package 
insert), except for certain recommendations in section V pertaining to FDA-approved patient 
labeling (e.g., Patient Information, Medication Guide, and Instructions for Use).2  This guidance 
does not provide specific labeling recommendations for interchangeable products (see 
section VIII of this guidance). 
 
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.  
 
 
II.  BACKGROUND 
 
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was enacted as part of 
the Patient Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148) on 
March 23, 2010.  The BPCI Act amends the PHS Act and other statutes to create an abbreviated 
licensure pathway for biological products shown to be biosimilar to or interchangeable with an 
                                                 
1 This guidance has been prepared by the Office of New Drugs, Therapeutic Biologics and Biosimilars Staff, in the 
Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and 
Research (CBER) at the Food and Drug Administration.  
 
2 Unless otherwise specified, the terms biosimilar product labeling and labeling as used in this guidance address 
only the prescribing information as described in 21 CFR 201.56 and 201.57. 
 
 
1  Contains Nonbinding Recommendations 
 
 
FDA-licensed reference product3 (see sections 7001 through 7003 of the Affordable Care Act).  
Section 351(k) of the PHS Act, added by the BPCI Act, sets forth the requirements for an 
application for a proposed biosimilar product and an application or a supplement for a proposed 
interchangeable product.   
 
Section 351(i) of the PHS Act defines biosimilarity to mean that the biological product is highly 
similar to the reference product notwithstanding minor differences in clinically inactive 
components and that there are no clinically meaningful differences between the biological 
product and the reference product in terms of the safety, purity, and potency of the product.   
 
To meet the standard for interchangeability, an applicant must provide sufficient information to 
demonstrate biosimilarity and also to demonstrate that the biological product can be expected to 
produce the same clinical result as the reference product in any given patient and, if the 
biological product is administered more than once to an individual, the risk in terms of safety or 
diminished efficacy of alternating or switching between the use of the biological product and the 
reference product is not greater than the risk of using the reference product without such 
alternation or switch (see section 351(k)(4) of the PHS Act).  Interchangeable products may be 
substituted for the reference product without the intervention of the prescribing health care 
provider (see section 351(i)(3) of the PHS Act).   
 
An application submitted under section 351(k) of the PHS Act must contain, among other things, 
information demonstrating that the biological product is biosimilar to a reference product based 
upon data derived from  
:
 
  Analytical studies that demonstrate that the biological product is highly similar to the 
reference product notwithstanding minor differences in clinically inactive components; 
 
  Animal studies (including the assessment of toxicity); and 
 
  A clinical study or studies (including the assessment of immunogenicity and 
pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, 
and potency in one or more appropriate conditions of use for which the reference product 
is licensed and intended to be used and for which licensure is sought for the biological 
product. 
 
Under the PHS Act, FDA has the discretion to determine that an element described above is 
unnecessary in a 351(k) application.   
 
Under FDA regulations, prescription drug labeling must provide adequate information to enable 
health care providers to use the drug safely and for the purposes for which it is intended; and to 
this end, the approved prescribing information summarizes the essential scientific information 
                                                 
3 Reference product means the single biological product licensed under section 351(a) of the PHS Act against which 
a biological product is evaluated in a 351(k) application (section 351(i)(4) of the PHS Act). 
 
 
2  Contains Nonbinding Recommendations 
 
 
needed by health care providers for the safe and effective use of a drug.4   Prescription drug 
labeling reflects FDAs finding of safety and effectiveness5,6 for the drug under the labeled 
conditions of use and facilitates prescribing decisions, thereby enabling the safe and effective use 
of drugs, including biological products, and reducing the likelihood of medication errors.   
 
 
III.  GENERAL PRINCIPLES FOR DRAFT LABELING OF PROPOSED 
BIOSIMILAR PRODUCTS (BIOSIMILAR PRODUCT LABELING) 
 
The goal of a biosimilar product development program is to demonstrate biosimilarity between 
the proposed product and the reference product  not to independently establish safety and 
effectiveness of the proposed product.  A demonstration of biosimilarity means, among other 
things, that FDA has determined that there are no clinically meaningful differences between the 
proposed product and the reference product in terms of safety, purity, and potency.7  Thus, 
FDAs finding of safety and effectiveness for the reference product, as reflected in its FDA-
approved prescribing information, may be relied upon to provide health care providers with the 
essential scientific information needed to facilitate prescribing decisions for the proposed 
biosimilar products labeled conditions of use (e.g., indication(s), dosing regimen(s)).  
Accordingly, FDA recommends that biosimilar product labeling incorporate relevant data and 
information from the reference product labeling, with appropriate modifications, such as those 
described in sections V and VI of this guidance.8   
 
Information and data from a clinical study of a proposed biosimilar product should be described 
in its labeling only when necessary to inform safe and effective use by a health care provider.  As 
a general matter, it is FDAs view that biosimilar product labeling should not include a 
description of or data from clinical studies conducted to support a demonstration of 
biosimilarity.9  Generally, clinical studies conducted to support a demonstration of biosimilarity 
                                                 
4 See 21 CFR 201.100 and 201.56(a)(1). 
 
5 The standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been 
interpreted to include effectiveness (see 21 CFR 600.3(s) and the guidance for industry Providing Clinical Evidence 
of Effectiveness for Human Drug and Biological Products).  We update guidances periodically.  For the most recent 
version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.   
 
6 In this guidance, we use the terms safety and effectiveness and safety, purity, and potency interchangeably in the 
discussions pertaining to biosimilar products.   
 
7 Section 351(i)(2) of the PHS Act. 
 
8 Sections V and VI of this guidance describe examples of areas in which the reference product labeling and 
biosimilar product labeling might differ. 
 
9 FDA posts on its website certain documents generated by FDA related to its review of a 351(k) application, as 
appropriate.  For products regulated by CDER, see Drugs@FDA 
(https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm).  For products regulated by CBER, see the CBER 
Freedom of Information Office Electronic Reading Room 
 
3  Contains Nonbinding Recommendations 
 
 
are not designed to support an independent demonstration of safety or effectiveness of the 
proposed biosimilar product and thus would generally not be expected to facilitate an 
understanding of product safety and effectiveness.  For example, the endpoints used in a clinical 
study conducted to support a demonstration of no clinically meaningful differences may not be 
the same endpoints evaluated to support licensure of the reference product and thus may not 
inform prescribing decisions regarding safety and effectiveness.  Similarly, the patient 
population may differ from the patient population studied in the clinical trials that supported the 
determination of safety and effectiveness of the reference product.  For example, subjects in a 
study conducted to support a demonstration of no clinically meaningful differences between the 
biosimilar product and the reference product may be healthy volunteers, or the condition of use 
studied may be one for which the reference product is not licensed or for which the applicant of 
the biosimilar product is not seeking licensure but for which sufficient data indicate that the 
population or condition of use is adequately sensitive to detect clinically meaningful differences 
between the products, should they exist.   
 
Because clinical studies conducted to support a demonstration of biosimilarity generally are not 
designed to support an independent demonstration of safety or effectiveness, such studies may be 
misinterpreted in the context of drug labeling, resulting in an inaccurate understanding of the 
risk-benefit profile of the biosimilar product.  Therefore, studies conducted to support 
biosimilarity generally should not be included in biosimilar product labeling.  Biosimilar product 
labeling should incorporate relevant data and information from the reference product labeling, 
including clinical data that supported FDAs finding of safety and effectiveness of the reference 
product. 
 
As required under 21 CFR 201.56(c)(1), biosimilar product labeling must meet the content and 
format requirements of the physician labeling rule (PLR) as described in 21 CFR 201.56(d) and 
201.57, regardless of the format of the reference product labeling.10  In addition, biosimilar 
product labeling must meet the content and format requirements of the pregnancy and lactation 
labeling final rule (PLLR) as described in 21 CFR 201.57(c)(9)(i) through (iii), regardless of 
whether the reference product must meet these requirements.11 
                                                 
(https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm129132.htm).  
Health care providers and others can refer to those documents if interested in FDAs review of data and information 
submitted in a 351(k) application to support biosimilarity. 
 
10 See the final rule Requirements on Content and Format of Labeling for Human Prescription Drug and Biological 
Products (71 FR 3922, January 24, 2006).  This rule is commonly referred to as the physician labeling rule because 
it addresses prescription drug labeling that is used by prescribing physicians and other health care providers.  Also 
see additional labeling guidances at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm.  
 
11 See the final rule Content and Format of Labeling for Human Prescription Drug and Biological Products; 
Requirements for Pregnancy and Lactation Labeling (79 FR 72064, December 4, 2014).  The final rule describes 
the implementation schedule for applications submitted on or after the effective date of the rule, applications 
pending at the time the rule became effective, and applications approved before the rule became effective (79 FR 
72064 at 7209596). 
 
 
4  Contains Nonbinding Recommendations 
 
 
 
 
IV.  SPECIFIC RECOMMENDATIONS ON CONTENT OF BIOSIMILAR PRODUCT 
LABELING 
 
FDA recommends that biosimilar product labeling incorporate relevant data and information 
from the reference product labeling, with appropriate modifications, as explained in sections V 
and VI of this guidance.  The relevant data and information from the reference product labeling 
that should be incorporated into the biosimilar product labeling will depend on whether the 
applicant is seeking licensure for all conditions of use (e.g., indication(s), dosing regimen(s)) or 
fewer than all conditions of use of the reference product for the biosimilar product.12   
 
In sections of the biosimilar product labeling that are based on the reference product labeling, it 
is anticipated that the text will be similar to the corresponding text in the reference product 
labeling.  Text based on the reference product labeling need not be identical to the reference 
product labeling and should reflect currently available information necessary for the safe and 
effective use of the biosimilar product.   Certain differences between the biosimilar and reference 
product labeling may be appropriate.  For example, biosimilar product labeling conforming to 
PLR and/or PLLR may differ from reference product labeling because the reference product 
labeling may not be required to conform to those requirements at the time of licensure of the 
biosimilar product.  In addition, biosimilar product labeling may include information specific to 
the biosimilar product that is necessary to inform safe and effective use of the product, including 
administration, preparation, storage, or safety information. This information may differ from that 
of the reference product labeling when it reflects differences between the biosimilar product and 
the reference product that do not preclude licensure of the biosimilar product.   
 
A.  Approaches to Product Identification 
 
In biosimilar product labeling, the approach to product identification depends on the context of 
the information being presented.  FDA acknowledges that there will be variations on the general 
concepts outlined in this section because the approach to product identification will depend on 
the specific statements.  The illustrative examples in this section use a fictional reference product 
JUNEXANT (replicamab-hjxf) and a fictional biosimilar product NEXSYMEO (replicamab-
cznm).    
 
 
                                                 
12 A biosimilar product applicant generally may seek licensure for fewer than all conditions of use for which the 
reference product is licensed.  The 351(k) application must include information demonstrating that the condition or  
conditions of use prescribed, recommended, or suggested in the proposed labeling submitted for the proposed 
biosimilar product have been previously licensed for the reference product (see section 351(k)(2)(A)(i)(III) of the 
PHS Act). 
 
 
5  Contains Nonbinding Recommendations 
 
 
1.  When use of the biosimilar product name is recommended: 
 
The biosimilar product name should be used in labeling text that is specific to the biosimilar 
product or that refers solely to the biosimilar product.  If a biosimilar product has a proprietary 
name, the proprietary name (e.g., NEXSYMEO) should be used in the appropriate sections.  
However, if a proprietary name is not available, or if referring to the drug substance (as 
discussed below), the biosimilar products proper name (e.g., replicamab-cznm) should be 
used.13     
 
The biosimilar products proprietary name (or, if a proprietary name is not available, the 
biosimilar products proper name) should be used in circumstances such as the following: 
 
  In sections where the information described is specific to the biosimilar product   This 
includes, but is not limited to, the following sections:  INDICATIONS AND USAGE, 
DOSAGE AND ADMINISTRATION, DESCRIPTION, and HOW 
SUPPLIED/STORAGE AND HANDLING.   
 
  For directive statements and recommendations for preventing, monitoring, managing, or 
mitigating risks (e.g., Discontinue NEXSYMEO in patients with [adverse reaction])    
Such statements are typically included in, but are not limited to, the BOXED 
WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and 
DRUG INTERACTIONS sections. 
 
The biosimilar products proper name should be used when referring to the drug substance.  An 
example would be to use the biosimilar products proper name in the DESCRIPTION section. 
 
2.  When use of the reference product name is recommended: 
 
When clinical studies or data derived from studies with the reference product are described in 
biosimilar product labeling, the reference products proper name  (e.g., replicamab-hjxf) should 
be used.  This information would typically be included in sections such as, but not limited to, 
ADVERSE REACTIONS (Clinical Trials Experience subsection) and CLINICAL STUDIES. 
 
3.  When use of the core name is recommended:14  
 
The overall risk-benefit profile of the reference product is relevant to the biosimilar product, 
even if a particular serious adverse reaction or other risk included in the reference product 
labeling may not have been reported with the biosimilar product at the time of licensure.  In 
labeling sections where the risk applies to both the biosimilar product and the reference product 
                                                 
13 The proper name is the nonproprietary name designated by FDA in the license for a biological product licensed 
under the PHS Act (see section 351(a)(1)(B)(i) of the PHS Act and 21 CFR 600.3(k)). 
 
14 Two examples of a core name are filgrastim and epoetin alfa.  The proper name for biological products will 
include a distinguishing suffix composed of four lowercase letters attached to the core name with a hyphen. 
 
6  Contains Nonbinding Recommendations 
 
 
(e.g., BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, 
ADVERSE REACTIONS (Postmarketing Experience subsection)), it would be appropriate to 
use the core name of the reference product followed by the word products (e.g., replicamab 
products) to convey, for instance, that a risk or other information necessary for the safe use of 
the product applies to both the biosimilar product and the reference product (see section IV.B of 
this guidance). 
 
For example, in WARNINGS AND PRECAUTIONS: 
 
Reference Product Labeling  Biosimilar Product Labeling 
Treatment with JUNEXANT increases  Treatment with replicamab products 
the risk of serious infections involving  increases the risk of serious infections 
various organ systems and sites that may  involving various organ systems and sites 
lead to hospitalization or death.  that may lead to hospitalization or death. 
 
4.  When use of more than one product name is recommended:  
 
There may be text appropriately based on the reference product labeling where more than one of 
these product identification approaches should be used to convey information accurately.  
Therefore, all text in biosimilar product labeling, even sections that have been based on reference 
product labeling, should be carefully evaluated for the most appropriate product identification 
approach.  In some cases, such as the following example, more than two of the approaches may 
be used: 
 
Replicamab products can cause hepatoxicity and acute hepatic failure.  In clinical trials of 
replicamab-hjxf, 10% of patients developed elevated ALT or AST greater than three 
times the upper limit of normal and 5% progressed to acute hepatic failure.  Evaluate 
serum transaminases (ALT and AST) and bilirubin at baseline and monthly during 
treatment with NEXSYMEO  . . .  
 
B.  Approaches to Content Presentation  
 
The labeling for the biosimilar product should be specific to the conditions of use (e.g., 
indication(s), dosing regimen(s)) sought for the biosimilar product and should be consistent with 
language previously approved for the reference product for those conditions of use.      
 
When a biosimilar product applicant obtains licensure for fewer than all conditions of use (e.g., 
indication(s), dosing regimen(s)) for which the reference product is licensed, certain text in the 
reference product labeling related to condition(s) of use for the reference product that are not 
licensed for the biosimilar product would generally not be included in the biosimilar product 
labeling.15  However, in certain circumstances it may be necessary to include information in the 
biosimilar product labeling relating to an indication(s) for which the biosimilar product is not 
                                                 
15 See Q.I.7 in the guidance for industry Biosimilars:  Questions and Answers Regarding Implementation of the 
Biologics Price Competition and Innovation Act of 2009.   
 
7  Contains Nonbinding Recommendations 
 
 
licensed, in order to help ensure safe use (e.g., when safety information in the reference product 
labeling is related to use of the product and is not specific to a particular licensed indication(s) or 
when information specific to only the biosimilar products indication(s) cannot be easily 
extracted).16  Such text should be written in a manner that does not imply that the biosimilar 
product is licensed for a reference product indication(s) or use(s) that has not been licensed for 
the biosimilar product.  In these circumstances, specific sections of labeling that could be 
affected include BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND 
PRECAUTIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, and USE IN SPECIFIC 
POPULATIONS. 
 
For example, for sections such as WARNINGS AND PRECAUTIONS and ADVERSE 
REACTIONS, the reference product labeling may pool and categorize events from all the 
reference product clinical trials for all the indications for which the reference product is licensed.  
In cases where the biosimilar product applicant is not seeking licensure for all the indications for 
which the reference product is licensed, the pooled data described in the reference product 
labeling should be included in the biosimilar product labeling in a manner that is not indication-
specific.  However, any text that refers to an indication for which the biosimilar product 
applicant is not currently seeking licensure and is included to ensure safe use of the biosimilar 
product should be revised to avoid an implication that the biosimilar has been licensed for that 
indication(s).    
 
C.  Approaches to Specific Sections of Biosimilar Product Labeling 
 
1.  HIGHLIGHTS OF PRESCRIBING INFORMATION (Highlights) 
 
a.  Initial U.S. approval 
 
The initial U.S. approval in the Highlights section is the year that the biosimilar product is 
licensed. 
 
b.  Biosimilarity statement  
 
FDA recommends including a statement, placed on the line immediately beneath the initial U.S. 
approval in the Highlights section, that the product is biosimilar to the reference product.  It 
should read as follows: 
 
[BIOSIMILAR PRODUCTS PROPRIETARY NAME (biosimilar products proper 
name)] is biosimilar* to [REFERENCE PRODUCTS PROPRIETARY NAME 
(reference products proper name)]. 
 
The asterisk should appear as a footnote symbol inserted after the word biosimilar.     
 
                                                 
16 See also 21 CFR 201.57(c)(6)(i). 
 
8  Contains Nonbinding Recommendations 
 
 
For example, for the fictitious product NEXSYMEO, the statement should read as follows: 
 
NEXSYMEO (replicamab-cznm) is biosimilar* to JUNEXANT (replicamab-hjxf).    
 
The footnote should appear at the end of the Highlights section (but above the Revision Date) 
and state the following: 
 
*Biosimilar means that the biological product is approved based on data demonstrating 
that it is highly similar to an FDA-approved biological product, known as a reference 
product, and that there are no clinically meaningful differences between the biosimilar 
product and the reference product.  Biosimilarity of [BIOSIMILAR PRODUCTS 
PROPRIETARY NAME] has been demonstrated for the condition(s) of use (e.g., 
indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of 
administration described in its Full Prescribing Information. 
 
2.  INDICATIONS AND USAGE 
 
Information in the INDICATIONS AND USAGE section should be specific to the licensed 
indications for the biosimilar product and should be consistent with information previously 
approved for the reference product.  The biosimilar product labeling should include text from the 
reference product labeling regarding any Limitations of Use relevant to the biosimilar products 
indication(s) (see section IV.B of this guidance for recommendations regarding text that refers to 
an indication for which licensure has not been sought by the biosimilar product applicant). 
 
  3.  ADVERSE REACTIONS, Immunogenicity 
 
Immunogenicity information for therapeutic protein products is usually placed in a subsection in 
the ADVERSE REACTIONS section entitled Immunogenicity.  To help health care providers 
interpret the significance of the information, the following or a similar statement should be 
included as the first paragraph in the subsection, preceding the immunogenicity data based on the 
reference product labeling: 
 
As with all therapeutic proteins, there is potential for immunogenicity.  The detection of 
antibody formation is highly dependent on the sensitivity and specificity of the assay.  
Additionally, the observed incidence of antibody (including neutralizing antibody) 
positivity in an assay may be influenced by several factors, including assay methodology, 
sample handling, timing of sample collection, concomitant medications, and underlying 
disease.  For these reasons, comparison of the incidence of antibodies in the studies 
described below with the incidence of antibodies in other studies or to other [core name] 
products may be misleading.  
 
 
9  Contains Nonbinding Recommendations 
 
 
V.  FDA-APPROVED PATIENT LABELING 
 
If a Medication Guide is required, applicants must follow existing Medication Guide regulations 
for biosimilar product labeling.17  If the FDA-approved patient labeling for the reference product 
includes Patient Information, applicants should develop Patient Information for the biosimilar 
product, incorporating relevant information from the Patient Information for the reference 
product, with appropriate modifications.  
 
If the FDA-approved patient labeling for the reference product includes Instructions for Use 
(IFU), the IFU for the proposed biosimilar product should incorporate relevant information from 
the IFU for the reference product and present the information in a similar manner.  The proposed 
IFU may differ from the IFU for the reference product where, for example, modified language or 
images are needed to describe the biosimilar product accurately.  If other changes are proposed 
beyond those necessary to describe the biosimilar product accurately, applicants should discuss 
proposed changes with the Agency, including whether such changes are appropriate and whether 
additional data to support such changes are warranted.  Additionally, if there are plans to conduct 
a human factors study and the applicant intends to submit a protocol for FDAs review, the 
applicant should seek FDA input on the proposed IFU when the human factors study protocol is 
submitted for FDA review.  A full and final review of proposed product labeling, including the 
IFU, will occur in the context of the planned 351(k) application and may be informed by any 
human factors study findings submitted or other relevant data included in the application. 
 
 
VI.  REVISING BIOSIMILAR PRODUCT LABELING 
 
A.  Updating Safety Information 
 
During the lifecycle of a biological product, changes in the labeling may be necessary to provide 
updated information needed for the safe and effective use of the product.  As the reference 
product and biosimilar product are used more widely or under diverse conditions, new 
information may become available.  This may include new risks or new information about 
known risks.  A biosimilar product application holder must comply with applicable requirements 
regarding adverse experience review, reporting, and recordkeeping (see 21 CFR 600.80).   
 
When new information becomes available that causes information in labeling to be inaccurate, 
false, or misleading, the application holder must take steps to change the content of its product 
labeling, in accordance with 21 CFR 601.12.18   All holders of marketing applications for 
biological products have an ongoing obligation to ensure their labeling is accurate and up to 
date.19  A biological product is misbranded, in violation of the Federal Food, Drug, and Cosmetic 
                                                 
17 See 21 CFR part 208. 
 
18 See, e.g., 21 CFR 201.56(a)(2):  In accordance with . . . [21 CFR 601.12], the labeling must be updated when 
new information becomes available that causes the labeling to become inaccurate, false, or misleading. 
 
19 Ibid. 
 
10  Contains Nonbinding Recommendations 
 
 
Act (FD&C Act), when its labeling is false or misleading; does not provide adequate directions 
for use and adequate warnings; or prescribes, recommends, or suggests a dosage, manner, 
frequency, or duration of use of the drug that is dangerous to health (see 21 U.S.C. 331(a) 
through (b) and 352(a), (f), and (j)).    
 
B.  Additional Conditions of Use 
 
FDA recognizes that a biosimilar product application holder may be interested in seeking 
licensure for an additional condition(s) of use after product licensure in the following scenarios: 
 
  The biosimilar product applicant originally obtained licensure for fewer than all of the 
conditions of use for which the reference product is licensed and is seeking licensure for 
one or more of the remaining licensed conditions of use of the reference product.   
 
  The biologics license application (BLA) holder for the reference product received 
licensure for a new condition of use for the reference product after the original licensure 
of the biosimilar product. 
 
The biosimilar product applicant may seek licensure for an additional condition(s) of use of the 
reference product in these scenarios by submitting a prior approval supplement(s) to the 351(k) 
application that contains the necessary data and information, including draft labeling revised to 
include the additional condition(s) of use sought.  For more information on how to support 
licensure of the biosimilar product for an additional condition(s) of use for which the reference 
product is licensed, refer to the guidance documents on biosimilar product development on 
FDAs website.20 
 
 
VII.  HOW TO SUBMIT INITIAL AND REVISED LABELING 
 
New BLAs and supplement submissions for biosimilar product labeling should include the 
following: 
 
  A clean version of reference product labeling that was used to develop the biosimilar 
product labeling 
 
  A tracked changes and annotated version of proposed biosimilar product labeling 
explaining the differences from the reference product labeling 
 
  A clean version of the proposed biosimilar product labeling 
  
 
                                                 
20 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm  
11  Contains Nonbinding Recommendations 
 
 
VIII.  INTERCHANGEABLE PRODUCTS 
 
Any specific recommendations for labeling for interchangeable products, including any 
interchangeability statement similar to the biosimilarity statement described in section IV.C.1.b 
of this guidance, will be provided in future guidance. 
12