Evaluation of Gastric pH-
Dependent Drug Interactions 
With Acid-Reducing Agents: 
Study Design, Data Analysis, 
and Clinical Implications 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2023 
Clinical Pharmacology 
 
    
Evaluation of Gastric pH-
Dependent Drug Interactions 
With Acid-Reducing Agents: 
Study Design, Data Analysis, 
and Clinical Implications 
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) 
 
March 2023 
Clinical Pharmacology 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  WHEN CLINICAL DDI STUDIES WITH ARAS SHOULD BE CONDUCTED ..... 2 
A.  Immediate-Release Products of Weak-Base Drugs................................................................2 
B.  Immediate-Release Products of Weak-Acid Drugs................................................................5 
C.  Modified-Release Products ...................................................................................................5 
III.  DESIGN AND CONDUCT OF CLINICAL DDI STUDIES ........................................ 5 
IV.  ALTERNATIVE APPROACHES FOR EVALUATING PH-DEPENDENT DDIS .. 7 
V.  EXTRAPOLATING CLINICAL DDI STUDY RESULTS .......................................... 8 
VI.  LABELING RECOMMENDATIONS.......................................................................... 10 
i  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Evaluation of Gastric pH-Dependent Drug Interactions With Acid-
Reducing Agents:  Study Design, Data Analysis, and Clinical 
Implications 
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  
 
Elevation of gastric pH by acid-reducing agents (ARAs) can affect the solubility and dissolution 
characteristics of some orally administered drugs.  As a result, concomitant administration of a 
drug with an ARA could alter the bioavailability of the drug, potentially resulting in a loss of 
efficacy for weak-base drugs or increased adverse events for weak-acid drugs.  ARAs such as 
antacids, histamine H -receptor antagonists (H  blockers), and proton pump inhibitors (PPIs) are 
2 2
widely used, and these drugs are available through prescription and also over the counter.2,3  
Consequently, there is a potential risk for clinically significant drug-drug interactions (DDIs) 
with concomitant administration of drugs with ARAs.  Therefore, it is important to assess the 
susceptibility of an investigational drug to DDIs mediated by gastric-pH changes (referred to as 
pH-dependent DDIs) early in drug development, characterize the DDI effect with clinical studies 
when needed, and communicate the relevant findings and mitigation options where available in 
the drug product labeling.   
 
This guidance describes the FDAs recommendations regarding:  (1) when clinical DDI studies 
with ARAs are needed; (2) the design of such clinical DDI studies; (3) how to interpret these 
study results; and (4) communicating these findings in drug product labeling.4  
 
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 Centers for Disease Control and Prevention's (CDC's) National Health and Nutrition Examination Survey, available 
at:  https://www.cdc.gov/nchs/data/hus/hus16.pdf#079 (accessed April 1, 2022). 
 
3 Zhang L, F Wu, SC Lee, H Zhao, and L Zhang, 2014, pH-Dependent Drug-Drug Interactions for Weak Base 
Drugs:  Potential Implications for New Drug Development, Clin Pharmacol Ther, 96(2):266-277. 
 
4 For general considerations regarding the evaluation of DDIs during drug development, see the FDA guidance 
entitled Clinical Drug Interaction Studies  Cytochrome P450 Enzymes and Transporters-Mediated Drug 
Interactions (January 2020).  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. 
1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
This guidance does not cover other DDI mechanisms for some ARAs such as reduced absorption 
due to the formation of chelate complexes (e.g., aluminum or magnesium hydroxides, calcium 
carbonate) for weak-acid drugs and decreased renal elimination of certain drugs as a result of the 
alkalinization of urine (e.g., sodium bicarbonate).  When appropriate, sponsors should evaluate 
the significance of these DDIs during drug development.  
 
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.  WHEN CLINICAL DDI STUDIES WITH ARAs SHOULD BE CONDUCTED 
 
Sponsors should assess the potential of pH-dependent DDIs for a drug during early development 
to better inform dosing of the drug with ARAs in subsequent clinical trials, especially for those 
indications where a significant proportion of patients are likely to be taking ARAs.  In general, if 
a drug is determined to have the potential for a pH-dependent DDI, the sponsor should conduct a 
clinical study to characterize the effect of ARAs on the pharmacokinetics of the investigational 
drug (see section III) or provide a rationale justifying the lack of a pH-dependent DDI based on 
in vitro, in silico, or clinical information.   
 
A.  Immediate-Release Products of Weak-Base Drugs 
 
Most drugs that have demonstrated pH-dependent DDIs are weak bases with low intrinsic 
aqueous solubility compared to the solubility needed to dissolve the clinical dose (i.e., the 
highest therapeutic dose divided by 250 mL).  The potential for an investigational drug to have 
an interaction with an ARA can be assessed in a stepwise manner based on the physicochemical 
properties of the drug substance and dissolution profiles of the drug product.5  A framework is 
presented below as an example for how to assess clinical DDI risk with ARAs (Figure 1).  
Sponsors should consult the appropriate review division if they pursue alternative strategies to 
evaluate pH-dependent DDIs.  
 
5 Miao L, F Wu, X Yang, YM Mousa, A Ramamoorthy, SC Lee, K Raines, L Zhang, and P Seo, 2022, Application 
of Solubility and Dissolution Profile Comparison for Prediction of Gastric pH-Mediated Drug-Drug Interactions, 
AAPS J, 24(35):https://doi.org/10.1208/s12248-022-00684-3. 
2 
  Contains Nonbinding Recommendations 
 
Figure 1.  A Framework to Assess Clinical DDI Risk with ARAs for Immediate-Release 
Products of Weak-Base Drugs 
 
 
rpm  revolutions per minute 
 
f2  similarity factor6  
 
a When appropriate, with justification, other dissolution parameters (e.g., apparatus, speed) and biorelevant 
media can be selected based on the properties of the drug substance and product.7,8,9,10  
 
6 For more information, see the FDA guidance entitled M9 Biopharmaceutics Classification System-Based 
Biowaivers (May 2021). 
 
7 Markopoulos C, CJ Andreas, M Vertzoni, J Dressman, C Reppas, 2015, In Vitro Simulation of Luminal Conditions 
for Evaluation of Performance of Oral Drug Products: Choosing the Appropriate Test Media, Eur J Pharm 
Biopharm, 93:173-82. 
 
8 Mann J, J Dressman, K Rosenblatt, L Ashworth, U Muenster, K Frank, P Hutchins, J Williams, L Klumpp, K 
Wielockx, P Berben, P Augustijns, R Holm, M Hofmann, S Patel, S Beato, K Ojala, I Tomaszewska, J Bruel, J 
Bulter, 2017, Validation of Dissolution Testing With Biorelevant Media: An OrBiTo Study, Mol Pharm, 
14(12):4192-4201. 
  
9 Dressman JB, M Vertzoni, K Goumas, C Reppas, 2007, Estimating Drug Solubility in the Gastrointestinal Tract, 
2007, Adv Drug Deliv Rev, 59(7):591-602. 
 
10 Segregur D, T Flanagan, J Mann, A Moir, EM Karlsson, M Hoch, D Carlile, S Sayah-Jeanne, J Dressman, 2019, 
Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Test to 
Reflect These Changes, J Pharm Sci, 108(11):3461-3477. 
  3  Contains Nonbinding Recommendations 
 
b The average AUC or C  of the investigational drug is anticipated to decrease by 25 percent or more in the 
max
presence of an ARA.11  The clinical significance of this decrease for an investigational drug should be 
determined based on the dose/exposure-efficacy relationship of individual drug.   
 
c Alternative approaches (e.g., population pharmacokinetic or physiologically based pharmacokinetic 
modeling, see section IV) can be considered. 
 
 
The assessments should account for the following additional considerations: 
 
  Solubility:  It is important to characterize the aqueous equilibrium solubility profile of 
the drug substance over a physiologically relevant pH range (e.g., 1.0 to 6.8).12  The pH 
values to conduct solubility measurements should be chosen, for example, in uniform 
increments (approximately one pH unit), such that any inflection in the profile is 
appropriately characterized.  Since the pH of the medium for measuring solubility could 
be altered by a tested drug and deviate from the initial pH, the pH of the solution should 
be measured and reported.  The dose used to calculate the reference solubility (i.e., dose 
divided by 250 mL) should be the maximum therapeutic dose intended to be marketed.   
 
  Formulation and dose used in a dissolution test:  Dissolution data can be generated for 
an initial formulation during early drug development to help assess the liability of pH-
dependent DDIs for an investigational drug.  In addition, the dissolution test should also 
be performed and reported for the formulation intended to be marketed at the maximum 
therapeutic dose.  
 
  Drugs intended to be taken only under fed condition:  Gastric pH is elevated upon 
food intake.  Thus, for a drug that is intended to be taken under fed conditions, the impact 
of gastric-pH changes should be evaluated by comparing solubility and dissolution 
profiles at conditions representing the fed state pH conditions to that of pH 6-6.8.  For 
example, pH 4-5 approximates the pH condition after a high-fat and high-calorie meal, 
and pH 2-3 reflects the pH condition after a light meal.13,14,15  However, assessing pH-
dependent DDI liability based on in vitro pH-solubility and -dissolution profiles can be 
 
11 Zhang L, F Wu, SC Lee, H Zhao, and L Zhang, 2014, pH-Dependent Drug-Drug Interactions for Weak Base 
Drugs:  Potential Implications for New Drug Development, Clin Pharmacol Ther, 96(2):266-277. 
 
12 See the FDA guidance entitled M9 Biopharmaceutics Classification System-Based Biowaivers (May 2021).    
 
13 Surofchy DD, LA Frassetto, and LZ Benet, 2019, Food, Acid Supplementation and Drug Absorption-A 
Complicated Gastric Mix:  A Randomized Control Trial, Pharm Res, 36(11):155. 
 
14 Koziolek M, F Schneider, M Grimm, C Mode, A Seekamp, T Roustom, W Siegmund, and W Weitschies, 
Intragastric pH and Pressure Profiles After Intake of the High-Caloric, High-Fat Meal as Used for Food-Effect 
Studies, 2015, J Control Release, 220(PT A):71-78. 
 
15 Simonian HP, L Vo, S Doma, RS Fisher, and HP Parkman, 2005, Regional Postprandial Differences in pH Within 
the Stomach and Gastroesophageal Junction, Dig Dis Sci, 50(12):2276-2285. 
  4  Contains Nonbinding Recommendations 
 
challenging because besides elevating pH, food intake stimulates secretion of bile acid 
which could increase drug solubility in the gastrointestinal tract.  Under these 
circumstances, sponsors should consult with review Divisions.   
 
B.  Immediate-Release Products of Weak-Acid Drugs   
 
There is less experience with the evaluation of the impact of pH-dependent DDIs for weak-acid 
drugs compared to weak-base drugs.  It is possible that co-administration with a PPI or a H  
2
blocker could result in a higher rate or extent (maximum concentration (C ) or area under the 
max
concentration time curve (AUC)) of absorption for weak-acid drugs with low solubility at pH 1-2 
and increased solubility at elevated pH.  However, based on data from currently approved weak-
acid drugs, the magnitude of pH-dependent DDIs for weak-acid drugs is generally small.  
Whether to conduct a clinical study depends on the safety profile or dose/exposure-safety 
relationship of a weak-acid drug.   
 
C.  Modified-Release Products   
 
Extended-release or delayed-release products with pH-sensitive release mechanisms have the 
potential for DDIs with ARAs.  There is very limited experience with clinical pH-dependent DDI 
evaluation for these modified-release products.  Sponsors should consult the appropriate review 
division for drugs that have a modified-release profile that could have a pH-dependent DDI 
liability. 
 
 
III.  DESIGN AND CONDUCT OF CLINICAL DDI STUDIES  
 
  Study population:  Generally, dedicated studies can be conducted in healthy subjects to 
characterize the interaction potential with ARAs.  Safety considerations could preclude 
the use of healthy subjects for testing certain drugs (e.g., cytotoxic drugs) in which case 
these studies should be performed in patients for whom the investigational drug is being 
developed.  The number of subjects included in a DDI study should be sufficient to 
provide a reliable estimate of the magnitude and variability of the interaction.   
 
  Study design:  Crossover studies (fixed-sequence or randomized) are preferred to reduce 
inter-subject variability.  A parallel study design can be considered if a drug has a long 
half-life.   
 
  Choice of ARAs:  Selection of ARAs and associated dosing regimens for DDI studies 
depends on the purpose (e.g., characterization of a worst-case scenario or identification of 
an appropriate mitigation strategy such as staggered administration).  Among the 
currently approved ARAs, PPIs result in prolonged effects on gastric pH; therefore, it is 
recommended that the study be conducted with or include a PPI.  Effects of other classes 
  5  Contains Nonbinding Recommendations 
 
of ARAs can be evaluated as alternatives as needed.  Some considerations are discussed 
in detail below.  
 
  PPIs:  Pre-treatment with PPIs for several days (e.g., 4 to 7 days) is needed to reach 
o
the pharmacodynamic steady state of PPIs before administering the investigational 
drug.  The effect of PPIs on gastric pH is long lasting, and thus staggered 
administration of an investigational drug with a PPI is not expected to mitigate the 
DDI risk (see section V for additional considerations).  
 
The effect of PPIs on gastric pH (e.g., mean pH over 24 hours, percentage of the time 
when the pH 4 in a 24-hour interval) is dependent on the individual PPI and its dose.  
It is preferable to select a PPI and a dose that is expected to provide a near maximum 
effect on pH elevation.16,17 
 
  H  blockers:  In general, administration of single or multiple doses of H  blockers 
o 2 2
ahead of the investigational drug (e.g., 2 hours) can maximize the pH-elevating 
effect.18,19  Since H  blockers result in a relatively shorter duration of pH increase 
2
than PPIs, the pH-dependent DDI risk could be reduced or avoided for a drug with 
staggered administration of H  blockers.  For example, administration of an 
2
investigational drug 2 hours before and 10 to 12 hours after dosing of H  blockers 
2
could mitigate the risk (see section V for additional considerations).  Such a strategy 
should be confirmed with a clinical study. 
 
  Antacids:  Concomitant administration of a single dose of an antacid could be used 
o
due to their direct gastric acid neutralizing effect.   
 
  Additional considerations:  Interacting mechanisms other than gastric-pH changes 
o
should be taken into consideration when choosing an ARA to study.  For example, 
omeprazole is a known inhibitor of CYP2C19, and cimetidine inhibits multiple CYP 
enzymes and transporters (e.g., CYP2D6, CYP3A4, MATE1 and MATE2/K).  It is 
preferable to select an ARA that does not exhibit other interacting mechanisms (see 
section I).  Also, an ARA should not be used in a DDI study if its pharmacokinetics 
are anticipated to be affected by the investigational drug.   
 
16 Miner P, PO Katz, Y Chen, M Sostek, 2003, Gastric Acid Control With Esomeprazole, Lansoprazole, 
Omeprazole, Pantoprazole, and Rabeprazole:  A Five-Way Crossover Study, Am J Gastronenterol, 98(12):2616-20. 
 
17 Kirchheiner J, S Glatt, U Fuhr, U Klotz, I Meineke, T Seufferlein, J Brockmoller, 2009, Relative Potency of 
Proton-Pump Inhibitors-Comparison of Effects on Intragastric pH, Eur J Clin Pharmacol, 65(1):9-31. 
 
18 Hedenstrom H, C Alm, M Kraft, A Grahnen, 1997, Intragastric pH After Oral Administration of Single Doses of 
Ranitidine Effervescent Tablets, Omeprazole Capsules and Famotidine Fast-Dissolving Tablets to Fasting Healthy 
Volunteers, Aliment Pharmacol Ther, 11(6):1137-41. 
 
19 Miner Jr, PB, LD Allgood, JM Grender, 2007, Comparison of Gastric pH with Omeprazole Magnesium 20.6 mg 
(Prilosec OTC) o.m. Famotidine 10 mg (Pepcid AC) b.d. and Famotidine 20 mg b.d. Over 14 Days of Treatment, 
Aliment Pharmacol Ther, 25(1):103-9. 
 
  6  Contains Nonbinding Recommendations 
 
 
  Dose:  To characterize the worst-case scenario, sponsors should select the highest dose of 
an ARA in the DDI study that is commonly used in clinical practice (e.g., 40 mg 
esomeprazole, 40 mg omeprazole, 40 mg pantoprazole).  The maximum recommended 
dose of an investigational drug that is intended for therapeutic use is recommended since 
it is more susceptible to pH-dependent DDI effects.  Sponsors should provide a 
justification if an alternative dose or dosing regimen is proposed.  
 
  Formulation:  The pH-dependent DDI effect can be formulation dependent.  Thus, a 
dedicated study is recommended with the to-be-marketed formulation of an 
investigational drug.  It is recognized that such a formulation might not be available 
during early drug development.  If a study is performed with an early formulation, the 
sponsor should provide a rationale that justifies why the pH-dependent DDI effect can be 
extrapolated to the to-be-marketed formulation.  
 
  Dosing frequency of investigational drug:  Single-dose administration of the 
investigational drug is acceptable, unless:  (1) there is a change in drug absorption after 
multiple doses; or (2) the study has to be conducted in patients, and single-dose 
administration is not beneficial to patients who need continuous treatment.   
 
  Food intake:  If an investigational drug is intended to be taken in the fasted state, the 
study should be conducted under fasted conditions.  If the investigational drug is intended 
to be taken without regard to food, the study should be conducted under fasted conditions 
as it is likely to represent the worst-case scenario.  If the investigational drug is intended 
to be taken with food, the study should be conducted under fed conditions that are 
consistent with late-phase clinical trials.  Administration of a drug with a high-fat meal 
could underestimate the pH-dependent DDI effect of ARAs compared to other types of 
food, since high-fat meals elevate the baseline gastric pH more than other meals and 
stimulate more secretion of bile acids which help solubilize drugs.   
 
  Pharmacokinetic sampling and data collection:  Pharmacokinetic (PK) sampling times 
should be sufficient to adequately characterize the AUC  (or steady-state AUC  
0-INF 0-TAU
for multiple-dose studies), the C , the time to reach C  (T ), and if clinically 
max max max
relevant, the minimal concentration (C ) or partial AUC of an investigational drug 
min
administered alone and when co-administered with an ARA.  Sponsors should also 
determine active metabolite concentrations if the metabolites contribute to the 
investigational drugs efficacy or safety.   
 
 
IV.  ALTERNATIVE APPROACHES FOR EVALUATING pH-DEPENDENT DDIs 
 
  Population pharmacokinetic analysis:  DDIs with ARAs can be evaluated within 
clinical trials using population pharmacokinetic analyses.  General design considerations 
  7  Contains Nonbinding Recommendations 
 
for such analyses can be found in the FDA guidance for industry entitled Population 
Pharmacokinetics (February 2022).  Some considerations specific to ARAs are discussed 
below. 
 
  Record of the dosing information:  The pH-dependent DDI effect is sensitive to 
o
the time of administration of the investigational drug relative to the ARA (e.g., H  
2
blockers or antacids) and can also be affected by the dose of ARAs and the intake of 
food.  Thus, it is critical to have a prospective plan to ensure that relevant 
information such as dose, timing, and duration of administration of the 
investigational drug and ARAs as well as food intake and content (e.g., fasted, high-
fat, normal, or light meal) are accurately captured. 
 
  PK sampling:  A pH-dependent DDI is expected to affect drug absorption; 
o
therefore, it is important to have sufficient blood sampling during the absorption 
phase of the investigational drug to better capture the potential DDI effect.  
 
  Data analysis:  Since the gastric pH-elevating effects of PPIs, H  blockers, and 
o 2
antacids have different durations, it is appropriate to evaluate these ARAs by classes 
(e.g., using PPIs, H  blockers, and antacids as three separate covariates).  If feasible, 
2
it can be useful to compare the systemic exposure of the drug between patients 
taking ARAs throughout the trial and patients taking ARAs periodically during the 
trial.  
 
  Physiologically based PK (PBPK) simulations:  In conjunction with the assessment 
framework outlined in Figure 1, PBPK simulations can sometimes be used to further 
assess the potential for pH-dependent DDIs.  PBPK approaches can also be useful to 
inform clinical study designs.  The applications of PBPK are still evolving and are 
continuously being evaluated by the FDA.  Therefore, sponsors are encouraged to consult 
the appropriate review division if they pursue a PBPK simulation approach to evaluate 
pH-dependent DDIs.  General considerations for using PBPK approaches in drug 
development can be found in the FDA guidance for industry entitled Physiologically 
Based Pharmacokinetic Analyses  Format and Content Guidance for Industry (August 
2018).20  
 
 
V.  EXTRAPOLATING CLINICAL DDI STUDY RESULTS 
 
  In general, the effects observed with an investigational drug and one ARA from a 
dedicated DDI study can be extrapolated to other ARAs within the same class (i.e., from 
one PPI to other PPIs at dose levels that achieve a similar gastric-pH elevating effect).   
 
 
20 Also see the FDA draft guidance entitled The Use of Physiologically Based Pharmacokinetic Analyses - 
Biopharmaceutics Applications for Oral Drug Product Development, Manufacturing Changes, and Controls 
(September 2020).  When final, this guidance will represent the Agencys current thinking on this topic. 
 
  8  Contains Nonbinding Recommendations 
 
  Extrapolation of the findings with an ARA to other in-class ARAs may be confounded 
when a dedicated DDI study is conducted with an ARA that has multiple interacting 
mechanisms besides a change in gastric pH. 
 
  A framework is presented below for extrapolating results from a dedicated study to 
develop labeling recommendations.  The framework depicts the example of a weak-base, 
immediate-release investigational drug product evaluated with a PPI (Figure 2).  
Sponsors should consult the appropriate review division if they pursue alternative 
strategies to evaluate pH-dependent DDIs.  
 
  In general, PPIs represent a worst-case scenario for pH-dependent DDIs due to their long-
lasting effects on gastric pH.  Thus, a negative result from a dedicated study with a PPI 
indicates the lack of a pH-dependent DDI for an investigational drug.  Whether PK 
results are considered as clinically significant should be determined based on the 
exposure-response (e.g., efficacy or safety) relationship of an investigational drug.  Refer 
to the FDA guidance for industry entitled Clinical Drug Interaction Studies  
Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020) 
for recommendations regarding interpreting the results of the DDI studies. 
 
  If the study of the investigational drug with a PPI demonstrates a clinically significant 
change in the exposure of an investigational drug, the FDA has the following 
recommendations regarding mitigation strategies and for conducting additional studies 
with the investigational drug to optimize DDI mitigation: 
 
  PPIs:  Avoid the use of the drug with PPIs.  Alternatively, the sponsor can consider 
o
conducting an additional study to evaluate the impact of a lower dose of a PPI.  
 
  H  blockers:  Avoid the use of the drug with H  blockers.  Alternatively, the sponsor 
o 2 2
can conduct an additional study with the investigational drug to evaluate one or more 
staggered dosing schedules to identify a clinically practical dosing regimen to 
mitigate the risk of pH-dependent DDIs. 
 
  Antacids:  Drug dosing can be staggered with antacids (e.g., administer the drug 2 
o
hours before or 2 hours after antacid use) because the antacid effect is short-term.21   
If needed, the sponsor can conduct a study to evaluate a shorter period of staggered 
dosing of the investigational drug with antacids.   
 
Such mitigation strategies should be appropriately communicated in labeling. 
 
 
 
 
21 Lin, MS, P Sun, HY Yu, 1998, Evaluation of Buffering Capacity and Acid Neutralizing-pH Time Profile of 
Antacids, J Formos Med Assoc, 97(10):704-10. 
 
  9  Contains Nonbinding Recommendations 
 
Figure 2.  Extrapolating Clinical DDI Study Results and Implications for Immediate-
Release Products of Weak-Base Drugs 
 
 
 
 
 
 
VI.  LABELING RECOMMENDATIONS 
 
The Prescribing Information must contain a summary of essential scientific information needed 
for the safe and effective use of the drug by the healthcare provider.22  For specific requirements 
and recommendations regarding how to incorporate DDI information in labeling, refer to 21 CFR 
201.57 and the following FDA guidances:23,24 
 
 
  Warnings and Precautions, Contraindications, and Boxed Warning Sections of 
o
Labeling for Prescription Drug and Biological Products  Content and Format 
(October 2011) 
 
  Clinical Pharmacology Section of Labeling for Human Prescription Drug and 
o
Biological Products  Content and Format (December 2016) 
 
 
22 21 CFR 201.56(a)(1). 
 
23 For additional human prescription drug labeling guidance documents, see the FDAs Labeling Resources for 
Human Prescription Drugs website (available at https://www.fda.gov/drugs/laws-acts-and-rules/fdas-labeling-
resources-human-prescription-drugs). 
 
24 Also see the FDA draft guidance entitled Dosage and Administration Section of Labeling for Human Prescription 
Drug and Biological Products  Content and Format (January 2023). When final, this guidance will represent the 
Agencys current thinking on this topic. 
  10  Contains Nonbinding Recommendations 
 
 
  Patient Counseling Information Section of Labeling for Human Prescription Drug 
o
and Biological Products  Content and Format (December 2014) 
 
  11