Hypertension:  Developing 
Fixed-Combination Drug 
Products for Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2018 
Clinical/Medical 
   
Hypertension:  Developing 
Fixed-Combination Drug 
Products for Treatment 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  BACKGROUND AND INTRODUCTION..................................................................... 1 
II.  COMBINATION RATIONALE AND DEMONSTRATING CONTRIBUTION OF 
COMPONENTS ................................................................................................................ 2 
III.  PHASE 3 TRIAL DESIGN AND LABELING CONSIDERATIONS ......................... 3 
  Contains Nonbinding Recommendations 
Hypertension:  Developing Fixed-Combination  
Drug Products for Treatment 
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.  BACKGROUND AND INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in the clinical development of fixed-
combination drug products2 for the treatment of hypertension. This guidance focuses on 
development of two-drug combinations of previously approved drugs, although the general 
approach is readily applicable to three or more drugs in combination. This guidance does not 
address combinations that include unapproved drug products.  
 
Hypertension is the most common chronic cardiovascular condition dealt with by primary care 
physicians and other health care practitioners. Hypertension increases the risk of stroke, coronary 
artery disease, heart failure, atrial fibrillation, and peripheral vascular disease.3, 4 Effective 
control of blood pressure has been shown to reduce the rate of these adverse outcomes. 
 
In general, most patients will require more than one drug product to achieve adequate blood 
pressure control. In the past, the usual approach was to give patients the drug products 
sequentially, that is, titrate the first drug product to its full dose, then add a second drug product 
and titrate to its full dose, etc. More recently, physicians commonly initiate treatments with less 
                                                 
1 This guidance has been prepared by the Division of Cardiovascular and Renal Products in the Center for Drug 
Evaluation and Research at the Food and Drug Administration.  
 
2 For purposes of this guidance, a fixed-combination drug product is one in which two or more active ingredients are 
combined at a fixed dosage in a single dosage form. 
 
3 Rapsomaniki E, Timmis A, George J, et al., 2014, Blood Pressure and Incidence of Twelve Cardiovascular 
Diseases: Lifetime Risks, Healthy Life-Years Lost, and Age-Specific Associations in 125 Million People, Lancet, 
383:18991911. 
 
4 Angeli F, Reboldi G, and Verdecchia P, 2014, Hypertension, Inflammation and Atrial Fibrillation, J Hypertens, 
32(3):480483. 
 
  1  Contains Nonbinding Recommendations 
than full doses of two drug products, with the goal of avoiding side effects but gaining most of 
the effect of each drug product and gaining an overall effect greater than the single drug products 
would have at their maximum doses. The American Society of Hypertension and the 
International Society of Hypertension have jointly recommended initiating treatment with two 
drug products if a patients untreated blood pressure is at least 20/10 millimeters of mercury 
(mmHg) above the target blood pressure.5 
 
In considering fixed-combination drug products, FDA recognizes the interest both in (1) 
developing combinations of less than full doses of drug products with distinct mechanisms of 
action (e.g., a diuretic combined with an angiotensin-converting enzyme inhibitor, an 
angiotensin-receptor blocker, or a beta blocker) that could be used as initial therapy; and (2) 
providing a range of combinations that allow dose titration to attain adequate blood pressure 
control.  
 
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. COMBINATION RATIONALE AND DEMONSTRATING CONTRIBUTION OF 
COMPONENTS 
 
  In selecting drug products for use in fixed-combination drug products, sponsors should 
consider previously approved antihypertensive drug products with reasonably distinct 
mechanisms of action. Because of the different mechanisms of action, the drug products 
individual components used together are likely to demonstrate additive blood pressure 
effects. In addition, if combinations include doses of each drug product below the 
maximum dose, dose-related adverse effects of the components can be expected to be 
reduced compared to uses of single drug products at their highest approved doses.  
 
  For sponsors to establish safety and effectiveness of combination drug products, 21 CFR 
300.50 (the combination rule) states that (1) each component must make a contribution to 
the claimed effects; and (2) the dosage of each component (amount, frequency, duration) 
is such that the combination is safe and effective for the intended patient population. In 
the past, sponsors satisfied the combination rule for combination antihypertensive drug 
products by examining the overall contribution of each drug in a large factorial study 
using multiple doses of each component (e.g., A and B) and showing that A plus B is 
greater than A and that A plus B is greater than B in an overall analysis of doses. 
Alternatively to conducting full factorial studies of multiple doses of each component of 
the combination, we believe a sponsor can demonstrate the independent contribution of 
the components in two additional ways: 
                                                 
5 Weber MA, Schiffrin EL, White WB, et al., 2014, Clinical Practice Guidelines for the Management of 
Hypertension in the Community: A Statement by the American Society of Hypertension and the International 
Society of Hypertension, J Hypertens, 32(1):315. 
  2  Contains Nonbinding Recommendations 
 
  In a factorial study comparing A plus B to A and to B at their highest approved doses, 

showing that each component contributes to the blood pressure effect, which shows 
that there is a difference between the mechanisms by which the drug products exert 
their effects.  
 
  Alternatively, in a factorial study comparing A plus B to A and to B, at the highest 

doses planned for the fixed-combination drug product (i.e., not necessarily the 
highest approved doses), showing that each component contributes to the blood 
pressure effect, provided that other evidence supports dissimilar mechanisms of action 
and the doses in the combination are reasonably high on their dose-response curves.  
 
  Once a sponsor addresses the combination rule with a study at the highest approved doses 
or at the highest doses proposed for use in combination, the sponsor does not need to 
study combinations of lower approved doses to satisfy the combination rule because the 
drug products independent effects at lower doses can be assumed.  
 
  Sponsors should adequately characterize the pharmacokinetics of each of the components 
when used in combination. 
 
  Sponsors that intend to market multiple dose combinations should pay attention to avoid 
marketing excessive numbers of combinations whose components exert similar blood 
pressure effects (e.g., a 5 mg/10 mg combination and a 7.5 mg/12.5 mg combination that 
both produce similar decreases in blood pressure).  
 
 
III.  PHASE 3 TRIAL DESIGN AND LABELING CONSIDERATIONS 
 
  In general, the FDA considers a single phase 3, double-blind, randomized trial to be 
sufficient for demonstrating effectiveness of combination drug products of previously 
approved antihypertensive drug products.  
 
  The study intended to show an effect of both components should be carried out in a 
population where initiating therapy with two drugs is appropriate. Sponsors should 
consult contemporary treatment guidelines. The higher the baseline blood pressure, the 
easier it will be to demonstrate blood pressure effects of the components, and the less 
likely it is that there will be intolerance to blood pressure reduction. 
 
  It is expected that significant effects are observed on both systolic and diastolic blood 
pressures. The effects should be assessed at the end of the dosing interval.  
 
  Sponsors should consider guidance intended to assist applicants in developing labeling 
for cardiovascular outcome claims for drugs that are indicated to treat hypertension.6  
                                                 
6 See the guidance for industry Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims. We 
update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
  3  Contains Nonbinding Recommendations 
 
  Sponsors should consider that labeling for two-drug combinations intended for initial use 
frequently includes model-based figures, as shown below in Figure 1, that describe the 
likelihood of reaching blood pressure goals on individual drug products or the 
combination, as a function of the baseline blood pressure.  
 
Figure 1:  Probability of Achieving Systolic Blood Pressure Less Than 140 mmHg 
 
 
  4