Clinical Drug
 
Interaction Studies 
With Combined Oral 
Contraceptives 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research 
 
June 2023 
Clinical Pharmacology 
 
   
Clinical Drug 
Interaction Studies 
With Combined Oral 
Contraceptives 
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) 
 
 June 2023 
Clinical Pharmacology 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  WHEN COC DDI STUDIES SHOULD BE CONDUCTED......................................... 2 
IV.  DESIGN AND CONDUCT OF CLINICAL COC DDI STUDIES .............................. 4 
V.  INTERPRETING THE RESULTS OF CLINICAL COC DDI STUDIES ................. 5 
VI.  EXTRAPOLATING THE RESULTS OF CLINICAL COC DDI STUDIES ............. 5 
VII.  LABELING RECOMMENDATIONS............................................................................ 6 
VIII.  ABBREVIATIONS ........................................................................................................... 8 
IX.  DEFINITIONS .................................................................................................................. 9 
X.  APPENDIX ...................................................................................................................... 10 
  Contains Nonbinding Recommendations 
 
Clinical Drug Interaction Studies With Combined Oral 
Contraceptives 
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 staff responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help sponsors of investigational new drug applications (INDs) and 
new drug applications (NDAs) evaluate the drug-drug interaction (DDI) effects of their 
investigational drugs on combined oral contraceptives (COCs), design DDI studies, and 
determine how to communicate DDI study results and risk mitigation strategies in labeling to 
address potential risks associated with increased or decreased exposure of COCs.   
 
Reference is made to the FDA guidances entitled Clinical Drug Interaction Studies  
Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020)2 for 
general principles in assessing the clinical DDI potential and In Vitro Drug Interaction Studies  
Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020) for in 
vitro experimental approaches to evaluate the interaction potential for investigational drugs that 
involve metabolizing enzymes and/or transporters.  This guidance focuses solely on specific 
recommendations relevant to metabolism-based drug interactions with COCs.  Other 
mechanisms that can cause an interaction (e.g., absorption-based) are not addressed in this 
guidance but should be considered by sponsors and investigators.  In addition, this guidance does 
not discuss DDIs with progestin-only pills (POPs) and contraceptives administered via non-oral 
routes (e.g., transdermal systems).  However, a DDI study with a COC could inform the impact 
on other types of contraceptives containing the same progestin. 
 
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 Clinical Pharmacology, Office of Translational Sciences, in the 
Center for Drug Evaluation and Research at the Food and Drug Administration. 
 
2 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. 
  1  Contains Nonbinding Recommendations 
 
 
 
II.  BACKGROUND 
 
COCs usually contain two synthetic steroid hormones, a progestin and an estrogen.  COCs are 
highly effective in preventing pregnancy when used correctly.  However, drug interactions with 
concomitant therapies can adversely impact the efficacy and safety of COCs by affecting 
enzymes involved in the metabolism of progestins and estrogens.  For example, decreased 
progestin concentrations can lead to unintended pregnancy (loss of efficacy).  In addition, 
decreased estrogen concentrations could cause breakthrough bleeding and may also adversely 
affect the efficacy of COCs.  Increased estrogen or progestin concentrations can increase the risk 
of venous thromboembolisms (VTEs), a rare but serious adverse event.     
 
Because COCs are widely used in females of reproductive potential, and many investigational 
drugs are co-prescribed with COCs after approval, the DDI potential between an investigational 
drug and COCs should be evaluated during drug development and communicated in the labeling.   
 
 
III.  SITUATIONS WHERE COC DDI STUDIES SHOULD BE CONDUCTED    
 
Cytochrome P450 (CYP) 3A is responsible for the metabolism of most commonly used 
progestins, although the relative contribution of CYP3A to the clearance of different progestins 
varies.3  Other metabolic enzymes, including CYP2C19, and certain isoforms of uridine 5'-
diphospho-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), are also involved in 
the metabolism of certain progestins.4  These enzymes share gene expression regulation 
pathways (e.g., pregnane X receptor, PXR) with CYP3A, although the induction of UGTs and 
SULTs is less well understood compared to CYPs.  In general, CYP3A is more sensitive to 
induction than other enzymes involved in the metabolism of progestins such as CYP2C19, 
UGTs, and SULTs.  Therefore, an investigational drugs induction effect on CYP3A can inform 
its potential to affect the pharmacokinetics of progestins in humans. 
 
The metabolism of ethinyl estradiol (EE), the most commonly used estrogen in COCs, involves 
multiple enzymes (i.e., CYP3A, CYP2C9, UGT1A1, and SULT1E1).4  Available information 
from clinical DDI studies suggests that moderate or strong inhibition of CYP3A combined with 
inhibition of other metabolic pathways of EE can significantly increase EE exposure levels 
higher than 50 mcg EE, the level at which there is an increased risk of serious adverse reactions, 
including VTEs.5 
 
 
3 Li L, X Yang, D Tran, SK Seo, and Y Lu. 2023, Combined Oral Contraceptives as Victims of Drug Interactions, 
Drug Metab Dispos, doi: 10.1124/dmd.122.000854 (online ahead of print).  
 
4 Zhang N, J Shon, M Kim, C Yu, L Zhang, S Huang, L Lee, D Tran, and L Li, 2018, Role of CYP3A4 in Oral 
Contraceptives Clearance, Clin Trans Sci, 11:251-260. 
 
5 Gerstman BB, JM Piper, DK Tomita, WJ Ferguson, BV Stadel, and FE Lundin, 1991, Oral Contraceptive Estrogen 
Dose and the Risk of Deep Venous Thromboembolic Disease, Am J Epidemiol, 133(1):32-37. 
  2  Contains Nonbinding Recommendations 
 
When an investigational drug for chronic use is expected to be co-administered with a COC in 
females of reproductive potential, and in vitro studies suggest that it is a CYP3A inducer or 
inhibitor, the sponsor can consider the following (see sections III.A-III.B) to determine whether a 
clinical DDI study should be conducted.  Also, for an investigational drug that is given for short-
term use, sponsors should discuss whether to conduct a DDI study with a COC with the 
appropriate FDA review division.  
 
A.  CYP3A Inducers 
 
When in vitro data suggest that the investigational drug has the potential to induce CYP3A in 
humans, the sponsor can address the DDI potential with COCs via one of the pathways below 
(see also Figure 1 in the Appendix):  
 
  If the investigational drug does not significantly decrease the area under the plasma 
concentration-time curve (AUC) of a sensitive CYP3A substrate (i.e., reducing the AUC 
of a sensitive CYP3A substrate by < 20 percent), then: 
 
  A COC DDI study might not be warranted when the investigational drug (and/or its 
o
metabolite when relevant) is not a CYP3A inhibitor in vitro or is not expected to 
inhibit CYP3A in humans.6  In this scenario, the lack of effect of the drug on a 
CYP3A substrate from the clinical DDI study indicates that the drug does not induce 
CYP3A in humans.  Hence, the drug is not expected to markedly decrease the 
systemic exposures of progestins/estrogens.   
 
  Further evaluation of the DDI potential with COCs could be recommended if the drug 
o
(and/or its metabolite when relevant) inhibits CYP3A in vitro and is expected to 
inhibit CYP3A in humans.  There could be situations where a drug is both a potent 
inducer and an inhibitor of CYP3A, so that the net effect on a sensitive CYP3A 
substrate is minimal or shown as inhibition.  However, other enzymes (e.g., UGT) 
involved in the metabolism of COCs can also be induced via a shared gene regulation 
pathway with CYP3A.  Therefore, if the drug does not inhibit these other enzymes, it 
could still decrease the AUC of COCs.  Sponsors are encouraged to consult with the 
appropriate FDA review division on whether to conduct a DDI study with a COC in 
such cases.  
 
  If the investigational drug is a weak CYP3A inducer (i.e., reducing the AUC of a 
sensitive CYP3A substrate by  20 to < 50 percent), then the sponsor should conduct a 
clinical DDI study with a COC to evaluate the effect of the investigational drug on the 
COC.  If the sponsor does not intend to conduct a COC DDI study, adequate justification 
should be provided.  Some factors that should be taken into consideration include:  (1) the 
projected magnitude of the interaction based on the study with a sensitive CYP3A 
substrate and other scientific evidence, such as a lack of concurrent CYP3A inhibition; 
and (2) whether the investigational drug shows nonclinical reproductive and 
 
6 Refer to the FDA guidance entitled In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions (January 2020).  
 
  3  Contains Nonbinding Recommendations 
 
developmental toxicity findings of concern to humans.7  Sponsors are encouraged to 
consult with the appropriate FDA review division in such cases. 
 
  If the investigational drug is a moderate CYP3A inducer (i.e., reduces the AUC of a 
sensitive CYP3A substrate by  50 to < 80 percent), sponsors should consider conducting 
a dedicated DDI study with a COC to evaluate the magnitude of exposure change of the 
COC.  In the absence of a dedicated DDI study, labeling should recommend avoiding 
concomitant use with COCs.  If concomitant use cannot be avoided, an alternative 
contraceptive that is not affected by enzyme inducers (e.g., intrauterine system) or 
additional nonhormonal contraception (e.g., condoms) should be recommended, since the 
drug has the potential to reduce the exposure, and possibly the efficacy, of COCs.  
 
  If an investigational drug is a strong CYP3A inducer (i.e., reduces the AUC of a sensitive 
CYP3A substrate by  80 percent), then significant reduction in exposures of COCs are 
likely to occur.  Therefore, the labeling should recommend avoiding concomitant use 
with COCs.  Furthermore, if the use of the CYP3A inducer is unavoidable, an alternative 
contraceptive method (e.g., intrauterine system) or additional nonhormonal contraception 
(e.g., condoms) should be recommended. 
 
When a drug is shown or anticipated to significantly reduce the systemic exposures of 
progestins/estrogens, further evaluations could be considered to characterize the time for the 
induction effect to disappear.  These additional evaluations could be helpful in identifying the 
duration that an alternative contraceptive method or additional nonhormonal contraception 
should be used after cessation of the investigational drug.   
 
B.  CYP3A Inhibitors  
 
COCs containing 50 mcg of EE or more have been reported to be associated with clinically 
meaningful increases in the risk of serious adverse reactions, such as VTEs, compared to 
products containing less than 50 mcg of EE.5  Therefore, an approximately 40 percent increase in 
EE concentration for COCs containing 35 mcg EE resulting in exposures similar to COCs 
containing 50 mcg EE could be clinically meaningful.  The sponsor should conduct a clinical 
COC DDI study (see Figure 2 in the Appendix) to quantify the magnitude of the DDI if:  (1) 
prior clinical DDI studies suggest that the investigational drug is a moderate or strong CYP3A 
inhibitor (i.e., it increases the AUC of a sensitive CYP3A substrate by 2-fold or more); and (2) in 
vitro or in vivo data suggest that the investigational drug also inhibits one or more other enzymes 
involved in the metabolism of EE (e.g., CYP2C9, UGT1A1, and SULT1E1).  
 
 
7  For more information, see the FDA guidance entitled S5(R3) Detection of Reproductive and 
Developmental Toxicity for Human Pharmaceuticals (May 2021 ICH Revision 3).   
 
  4  Contains Nonbinding Recommendations 
 
Inhibition of SULT1E1 could lead to a significant increase in EE exposures.8,9  Therefore, for 
investigational drugs that inhibit SULT1E1, a clinical DDI study with COCs should be 
considered or appropriate mitigation strategies should be proposed in labeling.  Due to very 
limited in vitro and clinical DDI studies conducted for SULTs so far, a cut-off value for in vitro-
to-in vivo extrapolation using basic equations similar to those recommended for CYP enzymes 
has not yet been established.   
 
C.  Teratogenic Drugs for Use in Females of Reproductive Potential 
 
For investigational drugs that have teratogenic potential,10,11 even if the results of in vitro or 
clinical DDI studies using a sensitive CYP3A substrate probe suggest weak or no induction 
potential on CYP3A, a COC DDI study should still be conducted.  For teratogenic drugs that are 
moderate or strong inducers of CYP3A, the approach of evaluating for DDIs with a COC is the 
same as that described in Figure 1 and section III.A.  For drugs that do not have teratogenic 
potential but are intended to be used with teratogenic drugs as a combination therapy, the 
sponsor should address the interaction potential with COCs as for teratogenic drugs.  Sponsors 
are encouraged to consult with the appropriate FDA review division. 
 
 
IV.  DESIGN AND CONDUCT OF CLINICAL COC DDI STUDIES 
 
A.  Study Population 
 
Premenopausal and postmenopausal females can be included in the DDI study; however, 
including premenopausal females allows for the assessment of pharmacodynamic (PD) endpoints 
that cannot be studied in postmenopausal subjects.  
 
The number of subjects included in a COC DDI study should be sufficient to provide a reliable 
estimate of the magnitude and variability of pharmacokinetic (PK) parameters. 
 
B.  Choice of COC 
 
 
8 Schwartz J, T Hunt, WB Smith, P Wong, P Larson, T Crumley, A Mehta, K Gottesdiener, N Agrawal, 2009, The 
Effect of Etoricoxib on the Pharmacokinetics of Oral Contraceptives in Healthy Participants, J Clin Pharmacol, 
49(7):807-15. 
 
9 Helmer E, N Karimian, K Van Assche, I Seghers, S Le Tallec, G Cherala, G Scott, FS Namour, 2022, Ziritaxestat 
Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition, Clin Pharmacol Ther, Jun 17. doi: 
10.1002/cpt.2689.  
 
10 Ahn MR, L Li, J Shon, ED Bashaw, and M-J Kim, 2016, Teratogenic Drugs and Their Drug Interactions with 
Hormonal Contraceptives, Clin Pharmacol Ther, 100:217-219. 
 
11 Akbar M, E Berry-Bibee, DL Blithe, RS Day, A Edelman, J Hochel, J Roxanne, M Kim, L Li, VS Purohit, JA 
Turpin, PE Scott, DG Strauss, H Sun, NK Tepper, L Zhang, and C Yu, 2018, FDA Public Meeting Report on Drug 
Interactions With Hormonal Contraceptives: Public Health and Drug Development Implications, J Clin Pharmacol,  
58:1655-1665. 
 
  5  Contains Nonbinding Recommendations 
 
Sponsors should use COCs that contain the most commonly used progestins in the United States, 
such as norethindrone (NET), norgestimate (NGM), levonorgestrel (LNG), or drospirenone 
(DRSP), combined with EE, so that the study results can directly inform the most likely clinical 
use.  Since DRSP is more sensitive to CYP3A modulation,12 a negative DDI result can be 
extrapolated to COCs containing progestins that are less sensitive to CYP3A induction (e.g., 
NET and LNG).  Alternatively, studying the COCs containing less sensitive progestin can 
maximize the chances of confirming the lack of impact of a drug as an inducer on the specific 
progestin but would limit the ability to extrapolate the study results to other progestins (see 
section VI).  
 
C.  Dose 
 
The investigational drug should be given at the highest proposed dose for labeling and should be 
dosed for a sufficient duration to ensure maximal modulation effect of the drug on metabolizing 
pathways of COCs. 
 
The COC can be dosed as either a single dose or as multiple doses for the PK assessment.  For 
PD assessments, multiple doses of a COC are recommended. 
 
D.  Study Design 
 
Fixed sequence or randomized crossover studies are preferred.  If these designs are not feasible, 
a parallel study design is acceptable.  
 
E.  PK Sampling 
 
Intensive PK sampling should be conducted for progestins and estrogens of the COC on PK 
assessment days to adequately characterize the maximum concentration (C ) and AUC.  In 
max
addition, PK sampling of the investigational drug is useful to ensure that adequate systemic 
exposures are achieved.     
 
F.  PD Assessments 
 
Currently, the dose/exposure-response relationships of progestin and estrogen for contraceptive 
efficacy are not fully established.  An approach for assessing PD parameters (e.g., estradiol, 
follicle stimulating hormone, luteinizing hormone, progesterone, and Hoogland score13) in 
addition to PK parameters can be considered, as it could provide supportive information when 
the geometric mean ratios of the systemic exposure parameters fall outside of the no-effect 
boundaries (see sections V and IX). 
 
 
12 Wiesinger H, S Klein, A Rottmann, B Nowotny, K Riecke, I Gashaw, M Brudny-Kloppel, R Fricke, J Hochel, and 
C Friedrich, 2020, The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of 
Five Progestins and Ethinylestradiol Compared to Midazolam, Clin Pharmacol Ther, 108(4):798-807. 
 
13 Hoogland HJ and SO Skouby, 1993, Ultrasound Evaluation of Ovarian Activity Under Oral Contraceptives, 
Contraception, 47(6):583-90. 
  6  Contains Nonbinding Recommendations 
 
Sponsors are encouraged to seek feedback from the appropriate FDA review division when they 
plan to conduct PK assessments using alternative study designs, including PD assessments. 
 
 
V.  INTERPRETING THE RESULTS OF CLINICAL COC DDI STUDIES 
 
The primary systemic exposure parameters should be reported, for example, the area under the 
plasma concentration-time curve (AUC) integrated across the dosing interval (AUC ) for 
0-TAU
multiple-dose studies, the AUC from time of administration extrapolated to infinity (AUC ) 
0-inf
for single-dose studies, and C .  
max
 
If the 90 percent confidence intervals (CIs) for the geometric mean ratio of the systemic 
exposure parameters fall entirely within the no-effect boundaries of 80 to 125 percent for the 
COC, no significant DDI is considered to be present.  If the 90 percent CIs are outside of the 80 
to 125 percent boundaries, the totality of evidence (e.g., safety and efficacy of the COC) should 
be considered when determining the clinical impact of the DDI on the COC.  For certain drugs 
such as teratogenic drugs, the clinical context and individual PK changes should be considered in 
addition to the CIs.  
 
 
VI.  EXTRAPOLATING THE RESULTS OF CLINICAL COC DDI STUDIES 
 
Although progestins including NET, LNG, NGM, or DRSP usually have the same direction of 
exposure change (increase versus decrease) when taken with the same investigational drug (i.e., a 
CYP3A inhibitor or inducer), quantitative extrapolation of DDI results from one progestin in a 
COC to another is challenging due to the different extent of CYP3A-mediated metabolism for 
each of these progestins.  
 
DRSP is a more sensitive CYP3A substrate compared to certain approved progestins such as 
NET and LNG.12  Therefore, the magnitude of exposure changes in DRSP due to CYP3A 
induction is expected to be larger than that for NET and LNG.  For an investigational drug that is 
a CYP3A inducer, if a clinical DDI study with a DRSP-containing COC shows no interaction, 
the investigational drug is less likely to affect the PK of progestins in NET- and LNG-containing 
COCs.   
 
 
VII.  LABELING RECOMMENDATIONS 
 
In general, the magnitude of the interaction and clinical consequences will guide labeling 
recommendations.  For example:14 
 
 
14 For more examples, see a related FDA draft guidance entitled Labeling for Combined Hormonal Contraceptives 
(December 2017).  When final, this guidance will represent the Agencys current thinking on this topic. 
 
  7  Contains Nonbinding Recommendations 
 
  If the increase in EE exposures leads to exposure levels exceeding those observed at an 
EE dose of 50 mcg, the drugs labeling should recommend avoiding concomitant use 
with COCs containing EE or to avoid use with a COC when EE exceeds a specific dose.   
 
  If the investigational drug is an enzyme inducer that will decrease progestin or estrogen 
exposure to an extent that can lead to reduced effectiveness of the COC, the drugs 
labeling should recommend avoiding concomitant use with COCs.  If use of the enzyme 
inducer is unavoidable, an alternative contraceptive that is not affected by enzyme 
inducers (e.g., an intrauterine system) or additional nonhormonal contraception (e.g., 
condoms) should be recommended in the labeling. 
 
COCs DDI information in the DRUG INTERACTIONS section of the drugs labeling:   
 
  Must describe clinically significant DDIs15 and the mechanism of the clinically 
significant DDIs16 (e.g., PK metabolism-based, PD interaction) if known, and should 
cross-reference to the CLINICAL PHARMACOLOGY17 section of labeling for details of 
the DDI study results 
 
  Should include the clinical effects of clinically significant DDIs 
 
  Must include specific practical instructions for preventing or managing clinically 
significant DDIs15 and should cross reference to the DOSAGE AND 
ADMINISTRATION section of labeling for detailed dosage modification information, if 
applicable 
 
When the COC DDI study results show no clinically significant DDI between a drug and the 
tested COC, the Pharmacokinetics subsection of CLINICAL PHARMACOLOGY section of the 
drugs labeling should include the following statement or similar statement:  No clinically 
significant differences in [drug substance] pharmacokinetics were observed when Drug-X was 
used concomitantly with Drug-Y.17 
 
When drug interaction information appears in multiple sections of labeling, applicants should 
cross-reference DDI information in accordance with the recommendations in the FDA guidance 
entitled Labeling for Human Prescription Drug and Biological Products  Implementing the 
PLR Content and Format Requirements (February 2013).   
 
 
15 21 CFR 201.57(c)(8)(i). 
 
16 21 CFR 201.57(c)(8)(i). 
 
17 For more information, see the FDA guidance entitled Clinical Pharmacology Section of Labeling for Human 
Prescription Drug and Biological Products  Content and Format (December 2016). 
 
  8  Contains Nonbinding Recommendations 
 
VIII.  ABBREVIATIONS 
 
AUC Area under the plasma concentration-time curve (AUC) from time of 
0-INF  
administration extrapolated to infinity  
 
AUC Area under the plasma concentration-time curve integrated across the 
0-TAU  
dosing interval 
 
COC  Combined oral contraceptive 
 
CIs   Confidence intervals 
 
CYP  Cytochrome P450 
 
DDI  Drug-drug interaction 
 
DRSP  Drospirenone 
 
EE    Ethinyl estradiol 
 
FDA  Food and Drug Administration 
 
IND        Investigational new drug application 
 
LNG  Levonorgestrel 
 
NDA  New drug application 
 
NET  Norethindrone  
 
NGM  Norgestimate 
 
PD   Pharmacodynamic 
 
PK   Pharmacokinetic   
 
PLR  Physician labeling rule 
 
POP  Progestin-only pill  
 
SULTs  Sulfotransferases  
 
UGTs  Uridine 5'-diphospho-glucuronosyltransferases 
 
VTE  Venous thromboembolism 
 
  9  Contains Nonbinding Recommendations 
 
IX.  DEFINITIONS 
 
Inducer  An inducer is a drug that decreases the AUC of substrates of a given 
metabolic pathway. 
 
Inhibitor  An inhibitor is a drug that increases the AUC of substrates of a given 
metabolic pathway. 
 
No-effect boundaries  No-effect boundaries represent the interval within which a change in a 
systemic exposure measure is considered not significant enough to warrant 
clinical action (e.g., dose or schedule adjustment, or additional therapeutic 
monitoring). 
 
 
 
  10  Contains Nonbinding Recommendations 
 
X.  APPENDIX 
 
Figures 1 and 2 show decision trees for determining when clinical COC DDI studies should be 
conducted. It should be noted that these decision trees are not applicable for investigational drugs 
that have teratogenic potential or will be used in combination with teratogenic drugs (see section 
III.C). 
 
Figure 1: COC DDI Study Decision Tree Based on CYP Induction Potential 
 
 
 
1 A COC DDI study might not be recommended when the drug (and/or its metabolite when relevant) is not a 
CYP3A inhibitor in vitro or is not expected to inhibit CYP3A in humans; further evaluation of the DDI potential 
with COCs could be recommended if the drug (and/or its metabolite when relevant) inhibits CYP3A in vitro and is 
expected to inhibit CYP3A in humans, given the potential for the inhibitory effect to counteract the induction effect. 
 
2 For strong CYP3A inducers, labeling should recommend avoiding the use of this drug in patients taking COCs.  If 
concomitant use cannot be avoided, use an alternative contraceptive that is not affected by enzyme inducers (e.g., 
intrauterine system) or additional nonhormonal contraception (e.g., condoms). 
 
3 For moderate CYP3A inducers, sponsors can consider conducting a dedicated study with a COC.  If the results 
suggest no significant decrease in exposure of the COC, concomitant use with the COC studied could be allowed.  In 
the absence of a dedicated study, labeling should recommend avoiding the use of this drug in patients taking COCs.  
If concomitant use cannot be avoided, use an alternative contraceptive that is not affected by enzyme inducers (e.g., 
intrauterine system) or additional nonhormonal contraception (e.g., condoms). 
 
4 For weak CYP3A inducers, if sponsors do not intend to conduct a COC DDI study, adequate justification should 
be provided.  Some factors that should be taken into consideration include:  (1) the projected magnitude of the 
interaction based on the study with a sensitive CYP3A substrate and other scientific evidence such as a lack of 
concurrent CYP3A inhibition; and (2) whether the investigational drug shows any nonclinical reproductive and 
developmental toxicity.  Sponsors are encouraged to consult the relevant review division in such cases. 
  11  Contains Nonbinding Recommendations 
 
Figure 2: COC DDI Study Decision Tree Based on CYP Inhibition Potential 
 
 
 
1 Inhibition of SULT1E1 alone can lead to a significant increase in EE exposures.  For drugs that inhibit SULT1E1, 
regardless of its inhibitory effect on CYP3A, a clinical DDI study with COCs should be considered or appropriate 
mitigation strategies should be proposed in labeling. 
  12