Clinical Pharmacology Section 
of Labeling for Human 
Prescription Drug and 
Biological Products  
Content and Format  
 
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) 
 
December 2016 
Labeling 
 
     
 
  Clinical Pharmacology Section 
of Labeling for Human 
Prescription Drug and 
Biological Products  
 Content and Format 
 
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
or 
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Email: ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/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) 
 
December 2016 
Labeling 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL PRINCIPLES FOR THE CLINICAL PHARMACOLOGY SECTION 2 
A.  Content and Organization ............................................................................................................. 2 
B.  Cross-Referencing of Clinical Pharmacology Information ........................................................ 4 
IV.      INFORMATION TO BE INCLUDED IN EACH CLINICAL PHARMACOLOGY 
SUBSECTION ................................................................................................................... 5 
A.   Subsection 12.1 Mechanism of Action .......................................................................................... 5 
B.  Subsection 12.2 Pharmacodynamics ............................................................................................ 6 
C.  Subsection 12.3 Pharmacokinetics................................................................................................ 8 
1. Absorption ........................................................................................................................................ 9 
2.  Distribution .................................................................................................................................... 10 
3.  Elimination ..................................................................................................................................... 10 
4.  Specific Populations....................................................................................................................... 11 
5.  Drug Interaction Studies ................................................................................................................ 13 
D.  Subsection 12.4 Microbiology ..................................................................................................... 14 
E.   Subsection 12.5 Pharmacogenomics ........................................................................................... 14 
V.  PRESENTATION OF INFORMATION ...................................................................... 15 
A.   Central Tendency and Variation ................................................................................................ 15 
B.  Presentation Format .................................................................................................................... 15 
VI.   PROCEDURAL INFORMATION................................................................................ 16 
i 
  Contains Nonbinding Recommendations 
 
Clinical Pharmacology Section of Labeling for Human Prescription 
Drug and Biological Products  Content and Format  
 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not create 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 offices responsible for this guidance as listed on the title 
page.  
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to assist applicants in preparing the CLINICAL PHARMACOLOGY 
section of prescription drug labeling (henceforth referred to as labeling) to meet regulatory 
requirements and ensure appropriate consistency in the format and content of this section for all 
prescription drugs approved by FDA.2,3  The guidance provides recommendations to applicants 
submitting new drug applications (NDAs) (including applications submitted under section 
505(b)(2) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)(2)), abbreviated new 
drug applications (ANDAs), supplements to approved NDAs, biologics license applications 
(BLAs), and supplements to BLAs, who intend to prepare or amend the clinical pharmacology 
information in the labeling for human prescription drugs.  Not all of the information identified in 
this guidance for inclusion in the CLINICAL PHARMACOLOGY section of labeling will be 
applicable for every drug; rather, the guidance provides a general framework and set of 
recommendations that should be adapted to specific drugs and their conditions of use.  For 
clinical pharmacology information presented in other parts of labeling (see section III.B of this 
                                                 
1 This guidance has been prepared by the Office of Clinical Pharmacology, Office of Translational Sciences in 
cooperation with the Labeling Development Team, Office of New Drugs, in the Center for Drug Evaluation and 
Research (CDER), and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration (FDA). 
 
2 This document provides guidance on the CLINICAL PHARMACOLOGY section of prescription drug labeling (21 
CFR 201.57(c)(13)) under the 2006 final rule that amended the requirements for the content and format of labeling 
for human prescription drug and biological products (commonly referred to as the Physician Labeling Rule (PLR)).  
See Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products (71 FR 
3922, January 24, 2006).   
 
3 This guidance applies to drugs, including biological products that are regulated as drugs.  For the purposes of this 
guidance, drug product or drug will be used to refer to human prescription drug and biological products that are 
regulated as drugs. 
  1  Contains Nonbinding Recommendations 
guidance), applicants should consult other relevant guidances for current perspectives on best 
labeling practices.4  
 
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 
 
Optimal pharmacotherapy is driven by an understanding of a drugs clinical pharmacology and 
the clinical context in which the drug will be used.  Important clinical pharmacology attributes to 
consider in therapeutic decision making include, but are not limited to, drug mechanism of action, 
pharmacodynamics (PD) (e.g., both on-target and off-target pathways), and pharmacokinetics 
(PK) in a variety of settings and specific populations.  
 
Clinical pharmacology information collected throughout a drugs life cycle can contribute to 
clinical decision making and may be appropriate for inclusion in a drugs labeling.  Specifically, 
we consider what clinical pharmacology information can be directly translated to prescribing 
decisions and provide specific recommendations that should be included in relevant sections of 
the labeling.  Examples of specific recommendations include strategies for dose selection, 
therapeutic individualization, and minimization of adverse reaction risk.  In these cases, 
supportive information (i.e., the clinical pharmacology basis for the specific recommendation) is 
generally expected to be concise to enable unambiguous application to patient care.  
Occasionally, depending on the complexity of the patient care recommendations, it is appropriate 
to include more detailed supportive information in the labeling.  The reason for including this 
information is to provide sufficient detail for the health care provider to determine the relevance 
of the information for a given patient or clinical scenario; this information is typically included 
in the CLINICAL PHARMACOLOGY section of labeling and is the main focus of this 
guidance. 
 
 
III.  GENERAL PRINCIPLES FOR THE CLINICAL PHARMACOLOGY SECTION  
 
A.  Content and Organization 
 
The CLINICAL PHARMACOLOGY section appears under Full Prescribing Information in the 
labeling.5  Information in this section should be presented in a way that is understandable to 
health care providers who may not have specific expertise in clinical pharmacology.  This 
                                                 
4 Additional labeling guidances are available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
5 21 CFR 201.57(c)(13) 
 
  2  Contains Nonbinding Recommendations 
section should generally include information on pertinent positive findings and may include 
pertinent negative findings that are informative for the safe and effective use of the drug.  The 
information presented must not be inaccurate, false, misleading, or promotional in tone;6 and 
subjective wording (e.g., fast or rapidly) should be avoided.  Indications or uses must not be 
implied or suggested in this section if not included in the INDICATIONS AND USAGE section  
and dosing regimens must not be implied or suggested if not included in the DOSAGE AND 
ADMINISTRATION section.7 
 
Specific content and format requirements for the CLINICAL PHARMACOLOGY section of the 
labeling are described in 21 CFR 201.57(c)(13)(i): 
 
This section must contain information relating to the human clinical pharmacology and 
actions of the drug in humans.  Pharmacologic information based on in vitro data using 
human biomaterials or pharmacologic animal models, or relevant details about in vivo 
study designs or results (e.g., drug interaction studies), may be included in this section if 
essential to understand dosing or drug interaction information presented in other sections 
of the labeling.  
 
The CLINICAL PHARMACOLOGY section of the labeling must contain the following 
subsections:8 
 
12.1 Mechanism of Action  
12.2 Pharmacodynamics 
   12.3 Pharmacokinetics 
 
In addition, the following standard subsections should be used when appropriate: 
 
    12.4 Microbiology 9 
    12.5 Pharmacogenomics10 
 
These subsection numbers should not be used for other subsections (i.e., the numbers 12.4 and 
12.5 are reserved for the Microbiology and Pharmacogenomics subsections, respectively).   
 
                                                 
6 21 CFR 201.56(a)(2). 
 
7 21 CFR 201.57(c)(2)(iv and v) and (c)(3)(ii), respectively. 
 
8 21 CFR 201.57(c)(13)(i). 
 
9 See FDA draft guidance for industry Microbiological Data for Systemic Antibacterial Drug Products  
Development, Analysis, and Presentation, which states that as provided for in the final rule Requirements on 
Content and Format of Labeling for Human Prescription Drug and Biological Products, the microbiology portion of 
the labeling can be added as subsection 12.4 (citing 71 FR 3922 and 21 CFR parts 201, 314, and 601).  When final, 
draft guidances referenced in this document will represent the FDAs current thinking on the guidance topic.   
 
10 See FDA guidance for industry Labeling for Human Prescription Drug and Biological Products  Implementing 
the PLR and Format Requirements. 
 
  3  Contains Nonbinding Recommendations 
Occasionally, the addition of subsections beyond 12.5 can be appropriate to convey important 
clinical pharmacology findings that are not included in subsections 12.1 through 12.5 because 
the information does not fit within the scope of these subsections, the information spans across 
multiple existing CLINICAL PHARMACOLOGY subsections, or is of sufficient breadth to 
affect readability of other key information within the section.  The additional subsections should 
be given sequential identifying numbers beginning with 12.6.  The title of the subsection should 
reflect the contents of the subsection.   
 
Subsections may also include the use of headings and subheadings that will help organize the 
information; we recommend using a consistent approach to distinguish headings and 
subheadings within sections (e.g., underlining for headings and italics for subheadings). 
Headings and subheadings should not be assigned a numerical identifier with an additional 
decimal point (e.g., 12.2.1). 
 
Units for all measures and parameters for clinical pharmacology related information should be 
consistent throughout the labeling. 
 
B.  Cross-Referencing of Clinical Pharmacology Information 
 
Detailed information on clinical pharmacology topics is included in the CLINICAL 
PHARMACOLOGY section, while other sections of labeling contain summary information and 
clinical recommendations that may be related to clinical pharmacology information.  Other FDA 
guidances provide additional instruction as to what specific information should be included in 
relevant sections of labeling.11  
 
Cross-referencing should be used in accordance with the FDA guidance for industry Labeling for 
Human Prescription Drug and Biological Products  Implementing the PLR and Format 
Requirements when specific clinical pharmacology information appears in multiple sections of 
labeling.  Although the preferred presentation of cross-referencing in the Full Prescribing 
Information is to use the section heading followed by the numerical identifier  (e.g. [see 
Warnings and Precautions (5.1)]), we recommend an exception when cross-referencing to 
subsection 12.4 Microbiology (i.e., use the subsection heading rather than the section heading  
[see Microbiology (12.4)]) because the term Microbiology more accurately reflects the 
information presented under this subsection (see section IV.A of this guidance). 
 
Detailed clinical recommendations based on PK or PD data should not be included in the 
CLINICAL PHARMACOLOGY section.  In general, if there are PK or PD findings that do not 
warrant clinical recommendations or where the clinical implications of the findings are not 
known, there should be no cross-reference to another section of labeling.  However, if positive 
findings are discussed in the CLINICAL PHARMACOLOGY section and a cross-reference to 
another section is not included, then an additional statement about the lack of clinical relevance 
of the information should be included (e.g., there is no clinical significance or the clinical 
                                                 
11 The guidances referenced in this document are available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
  4  Contains Nonbinding Recommendations 
significance of the findings is unknown).  Repetition of detailed information in multiple sections 
should be avoided. 
 
IV.      INFORMATION TO BE INCLUDED IN EACH CLINICAL PHARMACOLOGY 
SUBSECTION 
 
The pharmacologic and PK attributes of parent drug and metabolites that contribute to the overall 
efficacy or toxicity of a drug in a meaningful way should be included in the CLINICAL 
PHARMACOLOGY section of labeling.  If the drug is a racemate, a brief description of the 
racemic mixture followed by information about the clinical pharmacology of each enantiomer 
should be included in the appropriate subsection(s) if both are active and have different types of 
activity or different PK.  Intended or unintended effects due to additives (adjuvants, excipients, 
or preservatives) present in the drug formulation should also be included in this section.    
 
The subsections in the CLINICAL PHARMACOLOGY section can include quantitative 
information that is the result of specific clinical pharmacology studies, population analyses, or 
other modeling and simulation approaches (e.g., physiologically-based pharmacokinetic (PBPK) 
modeling).  
 
When describing a dosage that is outside the approved recommended dosage range (e.g., 
exposure-response, dose proportionality, and absorption kinetics), the dosage should be 
expressed in terms of the highest and lowest recommended dosage (e.g., 50 milligrams (mg) 
(0.5 times the lowest approved recommended dosage) to 400 mg (2 times the highest approved 
recommended dosage) assuming the approved recommended dosages are 100 mg and 200 mg). 
 
A.   Subsection 12.1 Mechanism of Action  
 
This subsection must summarize what is known about the drugs established mechanism(s) of 
action (MOA).12  The MOA must be discussed at various levels, including the cellular, receptor, 
or membrane level, tissue, the physiologic system level (target organ), and the whole body level, 
depending on what is known.13  Target selectivity should be described when data suggest that 
target selectivity might be related to toxicity or effectiveness.  Information from animals and in 
vitro studies can be included where helpful and clearly relevant to the human response.  
Although rarely needed, a brief description of disease pathophysiology may facilitate an 
understanding of the drugs pharmacology and its impact on that process, especially if the drug is 
intended to modulate the effects of an underlying molecular aberration. 
 
The subsection should include the MOA for the approved indication(s) or uses of the drug or 
about clinically significant adverse reactions or other potential safety hazards associated with the 
drug.  The MOA for indications or uses not included in the INDICATIONS AND USAGE 
section of the labeling must not be included.14  Speculative claims of untested MOAs and 
                                                 
12 21 CFR 201.57(c)(13)(i)(A). 
13 Id.  
14 21 CFR 201.57(c)(2)(iv and v). 
 
  5  Contains Nonbinding Recommendations 
unsupported suggestions of therapeutic advantages based on MOA may be false or misleading 
and, therefore, must be avoided.15  If different MOAs are the bases of response in different 
approved indications, the MOA should be summarized for each approved indication.  If the 
MOA to achieve the desired clinical effects is not known, a statement about the lack of this 
information must be included.16   
 
If the drug is an antimicrobial agent, the antimicrobial MOA should be described in subsection 
12.4 Microbiology, rather than in subsection 12.1 Mechanism of Action.  The subsection 12.1 
Mechanism of Action should include only a statement in the following form: 
 
 X is an anti- (e.g., bacterial, viral, as appropriate) drug [see Microbiology (12.4)].  
 
B.  Subsection 12.2 Pharmacodynamics 
 
This subsection must include a description of any biochemical or physiologic pharmacologic 
effect of the drug or active metabolites related to the drugs clinical effect or related to adverse 
effects or toxicity.17  This subsection should include a description of the drugs or its 
metabolites effect on relevant PD biomarkers or other relevant clinical measures.  The relevance 
of the PD biomarker is a function of how mechanistically related the biomarker is to the drugs 
clinical effect or toxicity.  
 
If data exist and are pertinent to drug use, the following information should be summarized for 
the drug and its active metabolites: 
 
  Principal PD effect(s) 
  Time of onset of the PD effect and time of peak PD effect 
  Whether or not the PD effect is reversible 
  Time to stable PD effect and whether this time is related to the attainment of steady 
state blood concentrations or reflects hysteresis (i.e., a delay between attainment of 
effective plasma concentration and drug effect) 
  Duration of the PD effect after drug withdrawal and potential for rebound effect 
  Differential PD effects in subpopulations 
  Whether the PD effects are dose- or exposure-dependent and the nature of the dose-
response or exposure-response relationship. This information should be expanded to 
support actionable therapeutic drug monitoring information described in other 
sections of the labeling (e.g., the DOSAGE AND ADMINISTRATION section) 
where applicable. Therapeutic drug monitoring information may be presented under a 
separate heading under this subsection if the breadth of information necessitates it to 
enhance clarity and readability of the information. 
                                                 
15 21 CFR 201.56(a)(2). 
 
16 21 CFR 201.57(c)(13)(i)(A). 
 
17 21 CFR 201.57(c)(13)(i)(B). 
 
  6  Contains Nonbinding Recommendations 
  Information supporting the clinical impact of anti-product antibody formation on PD 
without a clinically significant change in PK. If both PK and PD are affected by anti-
product antibody formation, information supporting the clinical impact of anti-
product antibody formation will be included in subsection 12.3 Pharmacokinetics. 
The clinical impact of anti-product antibody formation, however, is included in other 
sections of the labeling (e.g., ADVERSE REACTIONS, WARNINGS AND 
PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING sections). 
 
A concise description of key study designs and results of drug interaction or specific population 
studies with a clinically significant impact on PD that is independent of PK changes should be 
included in this subsection.  A list of relevant studied coadministered drugs assessed for drug 
interaction potential or specific populations assessed for potential factor effects without a 
clinically significant impact on meaningful PD measurements may be included in one or more 
summary sentences that convey the knowledge that clinically significant issues were not 
observed.  If PK changes cause the effect on PD, this information should be described in the 12.3 
Pharmacokinetics subsection. 
 
If there are no relevant PD data, or the PD effects are unknown, this subsection must contain a 
statement indicating this lack of information.18 
 
Additional information relevant to the 12.2 Pharmacodynamics subsection might include 
undesired PD effects with cross-reference to clinically important descriptions in sections such as 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, or USE IN SPECIFIC 
POPULATIONS where appropriate.  If it informs prescribing decisions, it should include 
information on PD effects demonstrated outside the approved recommended dosage range for a 
complete understanding of the exposure-response relationship.  For example, knowing that an 
adverse reaction is associated with concentrations higher than what is expected from the 
approved recommended dosage would be useful information for the health care provider.  
 
Nonclinical animal PD information should generally be included in subsection 13.2 Animal 
Toxicology and/or Pharmacology.  However, nonclinical PD data may be included in subsection 
12.2 Pharmacodynamics if it is necessary for the understanding of pharmacology data in 
humans. 
 
Subsection 12.2 Pharmacodynamics should typically include the heading Cardiac 
Electrophysiology. A drugs effect on the QT interval should be described under this heading, 
and should include the dose(s) studied or exposure range observed as well as any dose or 
exposure-response relationships identified.  If there are potential clinically significant risks 
associated with QT prolongation, these potential risks should be discussed in other sections of 
labeling (e.g., BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND 
PRECAUTIONS, and DRUG INTERACTIONS sections).   
 
If there is no effect of the drug on the QT interval, this should be stated under this Cardiac 
                                                 
18 21 CFR 201.57(c)(13)(i)(B). 
 
  7  Contains Nonbinding Recommendations 
Electrophysiology heading.  For example, if a thorough QT trial is negative, the following 
statement is recommended: At a dose X times the maximum approved recommended dose, 
Drug Y does not prolong the QT interval to any clinically relevant extent. 19  If the information 
is not known, the Cardiac Electrophysiology heading may be omitted.  
 
C.  Subsection 12.3 Pharmacokinetics 
 
This subsection should begin with a brief introduction that describes the general, clinically 
significant PK properties of the parent drug and its relevant metabolites, and any unique drug 
characteristics.  For example, this introduction may include PK linearity/nonlinearity over the 
range of studied doses and a drugs biopharmaceutics characteristics (e.g., modified release, 
orally disintegrating tablet).  In addition, if the drug is classified as a prodrug then this 
designation should also be stated here.  The introduction should also include clinically useful 
information on the expected exposure of the drug (e.g., the maximum plasma concentration 
(C ), area under the plasma drug concentration over time curve (AUC)) at the approved 
max
recommended dosage, time to steady state, accumulation ratio following multiple dosing, and 
changes in PK over time. 
 
Following the presentation of this general information, the 12.3 Pharmacokinetics subsection 
should include the following headings (if applicable) in this order:  
Absorption  
Distribution  
Elimination  
Specific Populations  
Drug Interaction Studies  
 
If a heading is not applicable, it should be omitted.  Headings or subheadings can be added as 
appropriate (e.g., Anti-Product Antibody Formation Affecting PK ).  Information included in the 
brief introduction should not be repeated under the headings and subheadings.  Alternative 
formats (e.g., tables and figures) may also be considered to present this information and the brief 
introduction information (see section V.B of this guidance).  
 
Available PK measures and parameters (e.g., clearance, volume of distribution, half-life) should 
be included in this subsection to provide context for the optimization of drug administration.  
The use of general terms such as systemic exposure should be avoided unless they are 
qualified in the labeling (e.g., systemic exposure (i.e., AUC)).  Information on intra- and 
intersubject variability, if known, should also be included if it is informative for clinical use of 
the drug.  Whether or not the drug is subject to polymorphic enzymes or transporters that affect 
absorption, distribution, or elimination (e.g., metabolism, excretion) should be stated under the 
respective headings with appropriate detail in subsection 12.5 Pharmacogenomics and a cross 
reference to, subsection 12.3 Pharmacokinetics.  If the drug is a transporter substrate, the specific 
transporter should be mentioned under the appropriate heading (e.g., Absorption, Distribution, or 
                                                 
19 See FDA guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Proarrhythmic Drugs. 
 
  8  Contains Nonbinding Recommendations 
Elimination) based on its location and roles.  If the transport of a drug is subject to genetic 
variability, the information should be included under the relevant heading in the 12.3 
Pharmacokinetics subsection and cross-referenced to the fuller discussion in subsection 12.5 
Pharmacogenomics. 
 
Although relative bioavailability may be a factor in the approvability of an application (e.g., 
505(b)(2) applications), the term bioequivalence or the comparative PK data generally should 
not be included in the labeling.  Instead, the applicant should include relevant PK measures and 
parameters that are important for the safe and effective use of the drug.  In certain cases, it may 
be clinically relevant to convey differences in concentration-time profiles (e.g., a comparison of 
the plasma concentration versus time profiles of modified-release and immediate-release 
formulations).  
 
For fixed dose combination products that include previously approved individual components, 
only relevant information that forms the basis of a dosing decision from the individual 
components approved labeling should be included in the labeling for the fixed dose 
combination.  For example, if a fixed dose combination product cannot be administered to 
patients with renal impairment, the labeling should only include the data to support the 
recommendation to not administer the drug product to patients with renal impairment.  General 
PK information relating to renal impairment should not be included for the individual component 
when it does not inform prescribing decisions for the fixed dose combination product.  
 
1.  Absorption 
 
This heading is applicable to oral and other nonintravenous routes of administration and should 
include information related to the rate and extent of absorption.  Other factors related to 
absorption should be described when applicable.  Examples include: 
 
  The presence, location (liver and/or intestine), and extent of first pass effect, or other 
mechanisms affecting bioavailability (e.g., chemical degradation, intestinal metabolic 
enzymes, or transporters) 
  A description of the absorption kinetics (i.e., linear or nonlinear) over the range of 
studied doses 
  Extent and sources of variability of absorption within and between individuals, if 
known  
  Clinical relevance of disease-related changes in absorption (e.g., due to fast or slow 
gastrointestinal transit, short bowel syndrome) 
  Differences in absorption for different injection or application sites 
 
The effect of food on the absorption of orally administered drugs should be described under a 
subheading called Effect of Food under the Absorption heading.  A description of the food(s) 
or meal(s) used with respect to total calories and composition (fat, carbohydrate, and protein 
content) should be stated.  Specific study results, such as the effect of food on important PK 
parameters, should be included.  If studies are conducted to assess the effect of the timing of 
meals on absorption, those study results should be included.  The impact of drugs that affect 
  9  Contains Nonbinding Recommendations 
absorption (e.g., acid reducing agents) should be included under the Drug Interaction Studies 
heading within 12.3 Pharmacokinetics.  
 
Specific instructions on how a drug is to be administered relative to the ingestion of food or a 
food substance should be included in the DOSAGE AND ADMINISTRATION section.  This 
information may also be included in other sections of labeling, such as WARNINGS AND 
PRECAUTIONS, as appropriate, depending on the nature of the effect.20 
 
2.   Distribution 
 
The drugs volume of distribution should be included under this heading.  Additional discussion 
should be included if the volume of distribution contributes to the understanding of the drugs 
activity or safety (e.g., a large volume of distribution contributes to a long terminal half-life that 
may need to be considered when stopping therapy).  Other study results related to a drugs 
systemic distribution should be described here (e.g., distribution into blood components, tissue or 
central nervous system).  A drugs protein binding should be described under this heading.  
 
3.   Elimination 
 
The Elimination heading should include an introductory paragraph followed by two subheadings: 
Metabolism and Excretion.  The introductory paragraph should include the drugs total body 
clearance with information related to relevant contributions to total clearance (for example, the 
percent of total clearance attributable to renal and nonrenal clearance pathways).  The drugs 
half-life should be stated here.  The half-life value reported should usually be the half-life based 
on the time to reach steady state (i.e., the effective half-life).  If a long terminal half-life is 
important from a safety or effectiveness standpoint, the long half-life should be noted here and 
any management strategies related to the long terminal half-life should be described in other 
appropriate sections of the labeling (e.g., WARNINGS AND PRECAUTIONS).  When a drug 
exhibits nonlinear elimination within the approved recommended dosage range, the dosage that 
is associated with the half-life should be included. 
   
The Metabolism subheading should include a description of the biotransformation pathways, 
including the contribution of specific enzymes and identification of major metabolites.  The 
source of this information (i.e., in vitro and/or in vivo studies) should be clearly stated.  If there 
is uncertainty in the identification of the metabolic pathways, then pathways that have been ruled 
out should be identified.  
 
A metabolites activity, if relevant, should be described, including its metabolite-to-parent 
exposure ratio and contribution to activity in relation to the parent drug.  For example, Two 
active Drug X metabolites, metabolite Y and metabolite Z, that are equipotent to the parent were 
identified in plasma, and their AUCs represent 25% and 11% of the parent AUC, respectively. 
 
The Excretion subheading should include the pathways and extent of parent and metabolite 
                                                 
20 See FDA guidance for industry Food-Effect Bioavailability and Fed Bioequivalence Studies. 
 
  10  Contains Nonbinding Recommendations 
excretion from the body, as defined by chemical measures or radiolabel (mass balance) studies.  
Mechanisms involved in the excretory process should be included.  For example, if a drug 
undergoes renal excretion, the mechanism of renal excretion should be described (e.g., 
glomerular filtration, active secretion, or reabsorption).  If transporters involved in the excretion 
process have been identified, their contribution should be included.  
 
4.   Specific Populations  
 
This heading should include results of studies or analyses that evaluate the potential for PK 
differences in subpopulations defined by age, sex, race/ethnicity, renal function, hepatic function, 
and pregnancy.  We recommend that the following subheadings be used for consistency unless 
the specific population was not assessed: Geriatric Patients, Pediatric Patients, Male and Female 
Patients, Racial or Ethnic Groups, Patients with Renal Impairment, Patients with Hepatic 
Impairment, and Pregnant Women.  Additional subheadings representing other specific 
populations (e.g., smokers, obese patients, or low-body weight patients) may be included if 
informative for clinical use of the drug.  A description of the studies and the results should be 
included under these subheadings.  Brevity is encouraged.  Explicit dosage modifications or 
population-specific therapeutic management should be included in other sections as appropriate 
(e.g., DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and USE IN 
SPECIFIC POPULATIONS) 
 
Information regarding lactation, including PK, must be provided in the 8.2 Lactation subsection 
of the USE IN SPECIFIC POPULATIONS section.21 
 
If there were no clinically significant PK changes in specific populations or if there were no PK 
studies or analyses, consider including these populations in one or more summary sentences as 
needed instead of listing all of the subpopulations under different subheadings.  For example:  
 
The pharmacokinetics of drug X were not altered in patients with mild renal 
impairment (i.e., estimated creatinine clearance (CLcr) by Cockcroft-Gault (C-G) 
equation:  60 to 89 mL/min), patients with any degree of hepatic impairment, or in 
geriatric patients.  The impact of more severe renal impairment with or without 
hemodialysis on the pharmacokinetics of Drug X is unknown.  
 
The lack of specific population information or PK change under this heading should not be 
repeated in the USE IN SPECIFIC POPULATIONS section.  However, in certain circumstances, 
the lack of specific population information may be included in the USE IN SPECIFIC 
POPULATIONS section (e.g., there are clinical relevant differences in recommendations for use 
of the drug in patients with mild and moderate renal impairment compared to the indicated 
population, but patients with severe renal impairment have not been studied). 
 
Preferred subheadings and recommendations are as follows: 
                                                 
21 See 21 CFR 201.57(c)(9)(ii); see also FDA draft guidance for industry and review staff Pregnancy, Lactation, and 
Reproductive Potential: Labeling for Human Prescription Drug and Biological ProductsContent and Format. 
 
  11  Contains Nonbinding Recommendations 
 
a.  Geriatric Patients  
 
Descriptions and results of PK studies and analyses conducted in subjects 65 years of age and 
older should be presented under this subheading.  Results should be compared to those obtained 
in younger adult populations where possible.  Analyses related to age can be included with age 
as a categorical variable or as a continuous variable.  In some cases, it may be relevant to use age 
breakpoints other than 65 years.  For example, if exposures are found to be much higher in 
patients older than 80 years, it would be appropriate to use 80 years of age as a breakpoint to 
describe the results.  If appropriate, ranges of ages could also be included to describe the results.  
 
b.  Pediatric Patients 
 
Pediatric PK information should appear under this subheading for approved pediatric indications 
and should include descriptions and results of studies and analyses to evaluate PK in pediatric 
patients from birth to less than 17 years of age. However, if applicable, pediatric PK information 
should appear under subsection 8.4 Pediatric Use when safety and effectiveness have not been 
established in the relevant pediatric population.22  PK exposure measures or parameter values 
should be summarized based on appropriate pediatric age groups.  For example, PK parameter 
values can be described as a function of age or maturity that reflects ontogenic development.  
 
c.  Male and Female Patients 
 
Descriptions and results of studies and analyses conducted to identify PK differences between 
male and female subjects should be presented under this subheading.  
   
d.  Racial or Ethnic Groups 
 
Descriptions and results of studies and analyses conducted to identify differences in PK among 
race/ethnicity groups should be presented under this subheading.23  
 
e.  Patients with Renal Impairment  
 
Descriptions and results of studies and analyses conducted to identify PK differences in subjects 
with varying degrees of renal impairment should be presented relative to the PK of the drug in 
subjects with normal renal function.  The results can be presented as a function of the renal 
function categories or by using a renal function measurement as a continuous variable.  The 
classification of renal function and how it was determined (e.g., C-G CLcr or modification of 
diet in renal disease (MDRD) estimated glomerular filtration rate (eGFR) equations) should be 
                                                 
22 See FDA draft guidance for industry and review staff Pediatric Information Incorporated into Human 
Prescription Drug and Biological Products Labeling. 
 
23 See FDA guidance for industry and Food and Drug Administration staff Collection of Race and Ethnicity Data in 
Clinical Trials. 
 
  12  Contains Nonbinding Recommendations 
included.  Changes in both the parent drug and relevant metabolites should be reported.  The 
effect of hemodialysis, continuous renal replacement therapies, and chronic peritoneal dialysis in 
clearing the parent drug and metabolites from the body should be described under this 
subheading, if known.  Relevant extracorporeal means of removing the drug from the body 
should also be described with clinical management recommendations in the OVERDOSAGE 
section of the labeling.24  
 
f.  Patients with Hepatic Impairment  
 
Descriptions and results of studies and analyses conducted to identify PK differences in subjects 
with varying degrees of hepatic impairment should be presented relative to the PK of the drug in 
subjects with normal hepatic function.  The categories of hepatic function should be defined and 
included.  Changes in both the parent drug and relevant metabolites should be reported.25  
 
g.  Pregnant Women  
 
Although studies conducted to evaluate the PK of a drug during pregnancy are not common, 
descriptions and results of any studies conducted and used to support risk statement(s) based on 
human data under the Risk Summary heading and Dose Adjustments During Pregnancy and the 
Postpartum Period subheading under the Clinical Considerations heading in subsection 8.1 
Pregnancy should be reported under this subheading.  The PK, including known differences 
pertinent to pregnancy, should be described as a function of trimester or gestational age, and any 
immediate postpartum effects on drug exposure should be reported under this subheading.26, 27   If 
there are PK data that support dosage adjustment(s) during pregnancy, a summary of this 
information must be provided in the 8.1 Pregnancy subsection of the USE IN SPECIFIC 
POPULATIONS28 section and the specific dosage adjustments must be provided in the 
DOSAGE AND ADMINISTRATION29 section.  
 
5.   Drug Interaction Studies 
 
                                                 
24 See FDA draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study 
Design, Data Analysis, and Impact on Dosing and Labeling. 
 
25 See FDA guidance for industry Pharmacokinetics in Patients with Impaired Hepatic Function:  Study Design, 
Data Analysis, and Impact on Dosing and Labeling. 
 
26 See the FDA draft guidance for industry Pharmacokinetics in Pregnancy  Study Design, Data Analysis, and 
Impact on Dosing and Labeling. 
 
27 See the FDA draft guidance for industry Pregnancy, Lactation, and Reproductive Potential: Labeling for Human 
Prescription Drug and Biological Products  Content and Format. 
 
28 21 CFR 201.57(c)(9)(i)(C)(2). 
 
29 21 CFR 201.57(c)(3)(i)(C). 
 
  13  Contains Nonbinding Recommendations 
Both positive and pertinent negative results from in vitro and/or in vivo studies conducted to 
evaluate drug interactions should be included under this heading.30  Brevity is encouraged.  A list 
of studied drugs with no clinically relevant interaction potential should be summarized in one or 
more sentences as needed to convey, without extensive elaboration, that no interactions were 
observed. 
 
A concise description of clinically significant drug interactions in addition to specific actionable 
instructions for preventing and managing the drug interactions should be included in the DRUG 
INTERACTIONS section of labeling. The specific actionable instructions should not be repeated 
in the CLINICAL PHARMACOLOGY section.  Other sections of labeling (e.g., DOSAGE AND 
ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, or 
SPECIFIC POPULATIONS31) may include information regarding drug interactions.  
 
D.  Subsection 12.4 Microbiology 
 
The 12.4 Microbiology subsection should include information relevant to the microbiology 
characteristics of the drug.32  
 
The antimicrobial MOA should be described in the 12.4 Microbiology subsection rather than in 
the 12.1 Mechanism of Action subsection.  Pharmacodynamic information of antimicrobials 
should not be included in the 12.4 Microbiology subsection, but instead it should be included in 
the 12.2 Pharmacodynamics subsection.  In addition, exposure-response relationships and 
relevant exposure relationships that are pertinent to the antimicrobial action of the drug, 
including impact on growth and resistance, should be included in the 12.2 Pharmacodynamics 
subsection using identifying headings (e.g., Exposure-Response, ExposureMinimal Inhibitory 
Concentration (MIC) Relationships, etc.).  
 
E.   Subsection 12.5 Pharmacogenomics 
 
If applicable, a 12.5 Pharmacogenomics subsection should be included in the CLINICAL 
PHARMACOLOGY section of the labeling and should include clinically relevant data or 
information on the effect of genetic variations affecting drug therapy.33 
                                                 
30 See the FDA draft guidance for industry Drug Interaction Studies  Study Design, Data Analysis, and Labeling 
Recommendations for detailed recommendations on the information that should be included under this heading, how 
to describe the results of positive drug interaction studies, and when it is important to cross-reference other sections 
of the labeling. 
 
31 When the results from a drug-hormonal contraceptive interaction study show the potential for altering the 
effectiveness of the contraceptive for a drug that also has a potential for adverse developmental outcomes, 
subsection 8.3 Females and Males of Reproductive Potential should note the impact of this drug interaction on 
contraception effectiveness, and cross-reference to the DRUG INTERACTIONS and CLINICAL 
PHARMACOLOGY sections as appropriate. 
 
32 See the FDA draft guidance for industry Microbiological Data for Systemic Antibacterial Drug Products  
Development, Analysis, and Presentation for information to be included in the 12.4 Microbiology subsection. 
 
  14  Contains Nonbinding Recommendations 
   
V.  PRESENTATION OF INFORMATION 
 
A.   Central Tendency and Variation 
 
Appropriate presentation of PK and PD data is critical to enable interpretation and translation of 
this information to individual patients and patient subgroups.  Calculation and comparison of 
some central tendency measure (e.g., mean exposure) between two specific populations (e.g., 
with and without hepatic impairment) is often the basis of dose modification recommendations in 
labeling.  Additionally, therapeutic individualization and personalized medicine increasingly call 
for consideration of response variability (i.e., variability in observed measurements). 
 
PK and PD values should be reported as mean (arithmetic or geometric) or median with a 
measure of dispersion (i.e., standard deviation and/or minimum and maximum values).  The 
presentation will depend on the distribution of the data, whether or not the data have been 
normalized, and/or which parameter is being reported (e.g., use of median may be more 
appropriate than mean for T ).   
max
 
The way information is presented can vary based on the attributes of the information that are 
important for clinical decisions.  The following are context-specific examples of clinically useful 
presentations of data distributions:  
  A histogram when knowledge of the frequency of observations across the entire range of 
results is important 
  The number and/or percentage of subjects with exposures above a certain value in 
situations when high exposures are related to safety concerns (or when therapeutic failure 
is a concern, the number/percentage of subjects with exposures below a certain value) 
  A cumulative distribution function to quantify the fraction of the population affected for 
threshold values of interest 
 
Skewed distributions of PK or PD data may have important therapeutic implications and should 
be evaluated for inclusion in labeling.  The following are examples of scenarios that should be 
evaluated for potential inclusion in labeling:  
  Presence of PK or PD outliers (especially if relevant to response or adverse reactions)  
  Bimodal (or multimodal) distribution of observations (which could represent more than 
one elimination process or polymorphic metabolism) 
  Skewness due to evaluation of only a subset of data (e.g., because out-of-range, near 
zero, or other criteria were applied to create a subset of the original data)  
 
B.  Presentation Format  
 
Information in the CLINICAL PHARMACOLOGY section of labeling is both qualitative and 
quantitative and can be presented in subsections as text, tables, and/or figures.  The approach that 
                                                                                                                                                             
33 See the FDA guidance for industry Clinical Pharmacogenomics:  Premarket Evaluation in Early-Phase Clinical 
Studies and Recommendations for Labeling for information to be included. 
 
  15  Contains Nonbinding Recommendations 
best ensures clarity and understanding for the healthcare provider should be used.  For example, 
general PK (e.g., linearity, accumulation, exposure parameters), absorption, distribution, and 
elimination information may be organized into a tabular format in lieu of text.  In addition, tables 
can be useful if it is important to highlight specific values or other data.  Figures may be useful to 
show trends and presence or absence of specific phenomena, especially when absolute data 
values are not critical to interpretation (e.g., for some drug interactions), or to explain 
relationships between independent and dependent variables and time-related phenomena (e.g., 
exposure-response relationships, concentration-time profiles, PD endpoint dynamics).  Tables 
and figures should be self-explanatory, clearly labeled, nonrepetitive, and consistently formatted.  
Text should generally not repeat the content of tables and figures. Headings or subheadings may 
be omitted if relevant information is presented in an organized table or figure. 
 
VI.   PROCEDURAL INFORMATION 
 
Submission of a labeling supplement for an approved drug is not required to solely address a 
minor formatting change (e.g., modifying or re-ordering heading or subheading titles) referred to 
in this guidance document that is not a regulatory requirement or a safety issue. When such 
minor formatting changes are incorporated into labeling, they must be documented by the 
applicant in the next annual report.34 
                                                 
34 21 CFR 314.70(d)(2)(x). 
  16