This document discusses the therapeutic index of antihistamines, which is defined as the benefit-to-risk ratio or efficacy-to-safety ratio that determines the range of doses where a drug is effective and safe. While second-generation antihistamines have similar efficacy for allergic rhinitis and urticaria, they differ in their safety profiles and therapeutic indices. Fexofenadine has one of the broadest therapeutic indices, having been shown to be effective at doses as low as 20 mg twice daily and not causing sedation or cardiac toxicity at doses as high as 690 mg twice daily. A broad therapeutic index is important considering potential drug interactions and situations where patients increase their dose in search of

1. 872 Vol. 2, No. 24 s November 2002
ABSTRACT
The therapeutic index of a histamine-1 (H1)-
antihistamine is the benefit-to-risk ratio of the
medication and defines the range of doses and
plasma concentrations over which the drug is
effective and safe. In allergic rhinoconjunctivitis
and urticaria, although the efficacy profiles of
currently available H1-antihistamines are similar,
these agents differ greatly with regard to safety,
and this contributes to their different therapeutic
indices. Compared with their first-generation pre-
decessors, the orally administered second-gener-
ation H1-antihistamines such as cetirizine,
desloratadine, fexofenadine, levocetirizine, and
loratadine have fewer central nervous system
(CNS) adverse effects. However, differences exist
among second-generation H1-antihistamines in
terms of their effect on the CNS, with some agents
having potential for dose-related CNS effects
when the manufacturer’s recommended dose is
exceeded. Similarly, in terms of cardiac safety,
although all currently marketed H1-antihistamines
are safer than astemizole or terfenadine, some of
the medications in this class may be more likely
than others to cause cardiac toxicity under cer-
tain circumstances. A broad therapeutic index is
important not only when considering the potential
effects of concomitant administration of medica-
tions, herbal products, and foods on the H1-anti-
histamine bioavailability and efficacy, but also
because patients may spontaneously increase
their H1-antihistamine dose in order to obtain
symptom relief. Fexofenadine is an example of
an H1-antihistamine that has a broad therapeutic
index beyond the manufacturer’s recommended
doses of 120 mg or 180 mg once daily.
Fexofenadine has been shown to be effective at
doses as low as 20 mg twice daily and to not
cause sedation or cardiac toxicity at doses as
high as 690 mg twice daily.
(Advanced Studies in Medicine. 2002;2(24):872-876)
A
ntihistamines are used as a first-line
treatment for seasonal and perennial
allergic rhinitis and chronic idiopathic
urticaria. The first-generation antihista-
mines, although effective in relieving
the symptoms of rhinitis and urticaria, are associated
with unwanted adverse effects such as sedation and
impaired psychomotor function because of their lack
of histamine-1 (H1)-receptor selectivity and, in partic-
ular, to their penetration into the central nervous sys-
tem (CNS). Second-generation antihistamines were
developed in the early 1980s with the aim of having
greater specificity for the H1-receptor and less CNS
penetration and, therefore, overcoming the adverse
effects observed with older agents. Consequently, all of
the currently available second-generation antihista-
mines exhibit broad therapeutic indices compared
PROCEEDINGS
THE VALUE OF A BROAD THERAPEUTIC
INDEX FOR ANTIHISTAMINES*
—
F. Estelle R. Simons, MD
*Based on a presentation given by Dr Simons at the XXI
Congress of the European Academy of Allergology and
Clinical Immunology.
Address correspondence to: FER Simons, Department of
Pediatrics & Child Health, University of Manitoba, 504D
John Buhler Research Center, 727 McDermot Avenue,
Winnipeg, Manitoba, Canada R3E 3P5.

2. Advanced Studies in Medicine s 873
PROCEEDINGS
with their first-generation counterparts. However, the
potential for CNS adverse effects still remain with
some of these agents. Therefore, consideration of the
therapeutic index when prescribing an antihistamine is
more important than consideration of either efficacy
or safety alone. This paper reviews the contributory
factors involved in the evaluation of the therapeutic
index of H1-antihistamines and focuses on the clinical
relevance of a broad therapeutic index.
THERAPEUTIC INDEX OF ANTIHISTAMINES
The therapeutic index of an H1-antihistamine is
the benefit-to-risk ratio, also referred to as the effi-
cacy-to-safety ratio, of the medication. This ratio
defines the range of doses and plasma concentrations
over which the drug is effective and safe. The lower
limit is determined by the minimally effective dose,
which is the lowest dose, or lowest plasma concen-
tration, associated with a beneficial clinical effect.
The upper limit is determined by safety, which is the
highest dose, or highest plasma concentration, toler-
ated without adverse pharmacologic effects. Most of
the second-generation antihistamines have a more
favorable therapeutic index than their predecessors
because of their greater relative safety. First-generation
antihistamines are still widely used, as indicated by
the results of a recent telephone survey that included
approximately 5000 individuals in communities across
the United States.1
The objective of the study was to
obtain information on the use of all medications,
including prescription drugs and over-the-counter
medications, as well as vitamins and natural supple-
ments, including herbal formulations, during the pre-
vious week. The survey showed that, of the 40 most
commonly used drugs, the sedating H1-antihistamines
diphenhydramine and chlorpheniramine were more
commonly used than the nonsedating second-genera-
tion agents loratadine and fexofenadine, suggesting
that further efforts are required to encourage patients
and physicians alike to use the newer nonsedating H1-
antihistamines.1
In addition, the survey indicated that
in any given week, most US adults take at least 1 pre-
scription or nonprescription medication, including
herbal formulations, and many people take multiple
agents, raising concerns regarding potential drug-drug
interactions that may occur.
The differences among the newer antihistamines
make evaluation of the therapeutic index an important
consideration when prescribing these agents. The ther-
apeutic index varies mainly according to the properties
of the H1-antihistamine itself, and these differences are
the focus of this review; however, it also depends on
several other factors, such as the formulation
(intranasal or oral), the disease (allergic rhinitis or
urticaria), and the population (pediatric or geriatric)
being treated.
ACTIVITY OF ANTIHISTAMINES
The activity of antihistamines has been determined
using different in vitro and in vivo models. For example,
measurement of H1-antihistamine concentrations in
plasma and skin and correlation of those concentrations
with their peripheral H1-receptor activity has been a use-
ful tool for determining onset of action, relative potency,
and duration of action as well as in developing optimal
recommendations for the dose and dose frequency of
individual agents. In a recent study, the extent of fexofen-
adine HCl (120 mg) and diphenhydramine (50 mg) dis-
tribution into the skin was examined, and the findings
were related to peripheral H1-receptor antagonist activi-
ty. The investigators found that while the skin levels of
fexofenadine correlated with H1-receptor activity,
diphenhydramine neither penetrated the skin nor pro-
duced substantial H1-receptor activity.2
In another study,
comparative analysis of the effects of the second-genera-
tion H1-antihistamines, levocetirizine, ebastine, fexofe-
nadine, and loratadine, showed that these agents were all
effective in suppressing the histamine-induced wheal and
flare response with levocetirizine exhibiting the greatest
antihistaminic activity.3
In addition, the efficacy profiles of H1-antihista-
mines have been established in numerous clinical stud-
ies. These studies have shown that, in general, the
different H1-antihistamines have similar efficacy in the
treatment of allergic rhinoconjunctivitis and
urticaria.4,5
For example, the H1-antihistamines, fex-
ofenadine, loratadine, desloratadine, and cetirizine,
have all proven to be effective for the treatment of
allergic rhinitis and urticaria.6-9
Furthermore, different
doses of the same H1-antihistamines generally have
similar efficacy profiles; that is, the dose-response
curve is relatively flat. For example, when fexofenadine
was administered to patients with chronic urticaria at
doses of 20, 60, 120, and 240 mg twice daily, all doses
significantly improved the mean total symptom score
compared with placebo.9

3. 874 Vol. 2, No. 24 s November 2002
PROCEEDINGS
SAFETY PROFILES OF ANTIHISTAMINES
In contrast to their similar efficacy profiles, currently
available H1-antihistamines differ greatly with regard to
safety, and this is the factor that primarily contributes to
their different therapeutic indices. A clean safety profile
is particularly important for those patient populations at
an increased risk for adverse effects, such as patients with
a small body mass, hepatic or renal dysfunction, pre-
existing CNS or cardiac disorders, and in those using
concomitant medications.
EFFECTS ON CNS AND CARDIOTOXICITY
First-generation H1-antihistamines such as diphen-
hydramine were associated with sedation and impair-
ment, which is thought to have been a result of their
ability to cross the blood-brain barrier and access CNS
H1-receptors; therefore, these agents have a narrow
therapeutic index. In contrast, orally administered
second-generation H1-antihistamines, such as ceti-
rizine, desloratadine, fexofenadine, levocetirizine,
and loratadine, have fewer CNS adverse effects
compared with their first-generation predecessors
and therefore have wider therapeutic indices. The
improvements in CNS effects with newer agents
have been confirmed in more than 50 randomized,
double-blind, placebo-controlled studies in which
objective measurements of sleep, learning, memory,
and psychomotor function have been made at regu-
lar intervals.10
Although these drugs have improved
features over first-generation antihistamines, sec-
ond-generation H1-receptor antagonists differ from
each other in terms of their CNS effects, and many
of them have the potential for dose-related CNS
effects when the manufacturer’s recommended dose
is exceeded.10
An example of the differences in CNS
effects between the antihistamines was shown in a
recent postmarketing surveillance study assessing
the sedative profiles of fexofenadine, loratadine, cet-
irizine, and acrivastine. In this study, although all 4
H1-antihistamines were associated with a low inci-
dence of sedation, the incidence was lower with fex-
ofenadine and loratadine than with cetirizine and
acrivastine.11
Fexofenadine is the only H1-antihistamine for
which safety has been extensively assessed over a
wide range of doses (Figure).12,13
Consistent with
other reports, a recent study by Hindmarch et al
showed that fexofenadine HCl at a dose of 360 mg
daily is demonstrably free from disruptive effects on
aspects of psychomotor and cognitive function.14
Furthermore, both qualitative and quantitative data
from positron-emission tomography studies have
shown that fexofenadine does not bind to the H1-
receptor in the brain, suggesting that it does not cross
the blood-brain barrier, thereby supporting the lack of
sedation or impairment observed with this antihista-
mine in clinical studies.15,16
Similarly, in terms of cardiac safety, although all
currently marketed H1-antihistamines are relatively
safe compared to astemizole or terfenadine, some of
the medications in this class, such as diphenhy-
dramine, may be more likely than others to cause car-
diac toxicity under certain circumstances, such as
when the manufacturer’s recommended dose is greatly
exceeded.17
Because of the concerns regarding the car-
Figure.The Range of Plasma Concentrations of Fexofenadine;
Data forWhich Safety Has Been Demonstrated18
Modified with permission from Russell T, Stoltz M, Weir S. Pharmacokinetics, phar-
macodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride
in healthy male volunteers. Clin Pharmacol Ther. 1998;64(6):612-621.
7000
6000
5000
4000
3000
2000
1000
0
0 6 12 18 24 30 36
800 mg
640 mg
480 mg
360 mg
280 mg
200 mg
130 mg
80 mg
40 mg
20 mg
Time (h)
MeanFexofenadinePlasmaConcentration(ng/mL)

4. diovascular safety of older agents, all newer agents are
extensively studied to assess potential cardiotoxic
effects. One of these agents, fexofenadine, was studied
in controlled clinical trials involving more than 6000
patients. The findings showed that this medication
does not cause QTc interval prolongation or cardio-
vascular side effects, including torsades de pointes.12
DRUG-DRUG INTERACTIONS
Absorption of H1-antihistamines from the gastroin-
testinal tract may be altered by concomitant administra-
tion of other agents. P-glycoprotein, a carrier protein
that belongs to the superfamily of adenosine triphos-
phate (ATP)-binding cassette proteins, is involved in fex-
ofenadine absorption. Inducers of this protein, such as
grapefruit juice, decrease absorption, while inhibitors
such as erythromycin or ketoconazole increase absorp-
tion.19
Because fexofenadine has a broad therapeutic
index, such effects are unlikely to be clinically relevant.
Evidence has suggested that the coadministration
of H1-antihistamines with certain agents, including
medications, herbal products, and foods, results in the
inhibition of metabolism and thereby accumulation of
these agents. For the first-generation antihistamines that
have a narrow therapeutic index, such increases in plas-
ma concentrations are associated with an increased risk
of adverse effects, such as sedation and even cardiotoxi-
city.20
Notably, differences exist among antihistamines
because of variations in their metabolic profile, ranging
from those that exhibit significant interactions with the
hepatic cytochrome P450 isoenzymes (such as astemi-
zole and terfenadine) to those that are practically devoid
of interactions in the P450 system (such as cetirizine,
fexofenadine, or levocetirizine).
In order to assess the clinical relevance of such
drug-drug interactions, evaluation of the therapeutic
index is particularly important. As described below, for
those antihistamines that exhibit a broad therapeutic
index, although such interactions may alter the plasma
H1-antihistamine concentration, this is unlikely to
translate into relevant changes in clinical outcomes.
THE CLINICAL SIGNIFICANCE OF
A WIDE THERAPEUTIC INDEX
Fexofenadine is an example of an H1-antihistamine
that has an extremely broad therapeutic index beyond
the recommended daily dose of 120 to 180 mg. In
clinical studies, the minimally effective dose of fexofe-
nadine is 20 mg twice daily, and even when adminis-
tered at doses of 360 mg, 2 to 3 times the usual rec-
ommended total daily dose, fexofenadine does not
cause CNS effects as assessed using objective testing.14
Furthermore, when doses of 690 mg twice daily,
6 times the recommended daily dose, were given in
clinical studies, fexofenadine was not associated with
subjective sedation, and steady-state plasma concen-
trations of up to 4900 ng/mL were shown to be well
tolerated.13,18
Investigations have also shown that fex-
ofenadine does not cause cardiovascular effects: single
(up to 800 mg daily) or multiple (up to 690 mg twice
daily for a period of 28 days) doses of fexofenadine
administered to healthy individuals produced no clin-
ically significant changes in cardiac conductance.12
A broad therapeutic index is valuable for an H1-
antihistamine, not only in terms of potential effects of
drug-drug interactions but also in situations where
overcompliance occurs; that is, when patients increase
their H1-antihistamine dose in order to obtain symp-
tom relief. For drugs with a broad therapeutic index,
even if the recommended dose is exceeded, the patient
is unlikely to be at risk from adverse effects.
Evaluation of the therapeutic index is also impor-
tant given the recent interest in the potential use of
antihistamines in the treatment of asthma. In many of
the clinical studies that have demonstrated the relief of
asthma symptoms, H1-antihistamines have been given
in higher doses than those used in the treatment of
allergic rhinitis.21
Therefore, an antihistamine with a
broad therapeutic index offers greater potential in
terms of flexible dosing for the treatment of other
allergic diseases, such as asthma, compared with a drug
that has a narrow therapeutic index.
CONCLUSION
Analysis of the efficacy and safety of antihistamines is
essential for determining the therapeutic index of these
agents, and this is a more appropriate measure than con-
sidering either efficacy or safety alone. Because second-
generation antihistamines have demonstrated significant
efficacy in clinical studies, their therapeutic indices are
determined primarily by safety considerations.
Fexofenadine is an example of an antihistamine with a
wide therapeutic index, offering potential flexibility of
dosing without increased safety concerns. In the future,
evaluating the therapeutic index for all antihistamines in
various patient populations will be important so that
these agents can be optimally prescribed.
Advanced Studies in Medicine s 875
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5. 876 Vol. 2, No. 24 s November 2002
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