Ann Allergy Asthma Immunol 131 (2023) 412−420

Contents lists available at ScienceDirect

CME Review

Evidence-based use of antihistamines for treatment of allergic

conditions

Sophia Linton, BSc*,y; Lubnaa Hossenbaccus, MSc*,y; Anne K. Ellis, MD, MSc, FRCP(C), FAAAAI*,y
* Department of Medicine, Queen’s University, Kingston, Ontario, Canada
y
Kingston General Health Research Institute—Allergy Research Unit, Kingston, Ontario, Canada

Key Messages
 Histamine is a major player in the allergic response; following mast cell degranulation, histamine binds primarily to H1 receptors, which
results in bronchoconstriction, nociception, and vasodilatation.
 Second-generation antihistamines are superior to first-generation antihistamines due to high H1 receptor selectivity, low brain permeabil-
ity, and longer durations of action with less unwanted adverse effects.
 The use of antihistamines is essential for managing allergic rhinitis; they are the first-line therapy and have the potential to be used in
combination with corticosteroids.
 Antihistamines are also the first-line therapy for urticaria and can be used with add-on treatments, such as biologics.
 For anaphylaxis and allergic asthma, antihistamines are adjunctive, optional treatments used only to manage secondary symptoms.

A R T I C L E I N F O A B S T R A C T

Article history: Available since the 1940s, H1 antihistamines are mainstay treatments for allergic conditions such as allergic rhi-
Received for publication May 8, 2023. nitis and urticaria. They function as inverse agonists that bind to the H1 receptor to inhibit histamine-induced
Received in revised form July 10, 2023. inflammation. The older, first-generation drugs are no longer recommended for patient use because of their
Accepted for publication July 13, 2023.
well-documented negative adverse effect profile. Evidence has been accumulating to support a newer generation
of H1 antihistamines in oral and intranasal formulations, including in combination with intranasal corticoste-
roids. The literature is replete with large meta-analyses and systematic reviews establishing the safety and effi-
cacy of second-generation H1 antihistamines in adult and pediatric allergic rhinitis populations, including
combination nasal spray agents (eg, MP29-02 or MP-AzeFlu). Although intraclass differences do exist, patient
preference, access, and costs should be the priority. Robust data on the regular, not as needed use of H1 antihist-
amines for urticaria have been published, including in the management of children and pregnant or lactating
women. In addition, H1 antihistamines can be used in other related allergic conditions, such as the secondary
symptoms of anaphylaxis, to provide patients with greater comfort, including in allergic asthma, depending on
the individual.
© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction histamine effects in allergic inflammation are mediated through the

H1 receptor including bronchoconstriction, nociception, vasodilata-
Histamine is a major player in the biologic events contributing to
tion, and cellular migration.1
an allergic reaction. It is released primarily from mast cell degranula-
H1 antihistamines block the proinflammatory actions of histamine
tion, which can be either immunoglobulin (Ig)E-dependent or non-
by acting as inverse agonists to down-regulate the H1 receptor.2 Oral
IgE dependent, and then can bind to histamine receptors (H1R-H4R)
H1 antihistamines have been on the market since the 1940s. These
expressed on various tissues and cells. Most of the important
agents are classified into first-generation and second-generation
antihistamines based on their ability to cross the blood-brain bar-
Address correspondence to: Anne K. Ellis, MD, MSc, FRCP(C), FAAAAI, Watkins 1D, rier.3 First-generation drugs bind the H1 receptors on neurons and
Kingston Health Science Centre—Kingston General Hospital, 76 Stuart Street, Kingston subsequently cause sedation, impaired concentration, memory
Ontario, Canada K7L 2V7 E-mail: [email protected].

https://doi.org/10.1016/j.anai.2023.07.019
1081-1206/© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420 413

Instructions
Credit can now be obtained, free for a limited time, by reading the review article and completing all activity components. Please note the
instructions listed below:
 Review the target audience, learning objectives and all disclosures.
 Complete the pre-test.
 Read the article and reflect on all content as to how it may be applicable to your practice.
 Complete the post-test/evaluation and claim credit earned. At this time, physicians will have earned up to 1.0 AMA PRA Category 1 CreditTM.
The minimum passing score on the post-test is 70%.
Overall Purpose
Participants will be able to demonstrate increased knowledge of the clinical treatment of allergy/asthma/immunology and be able to apply
new information to their own practices.
Learning Objectives
At the conclusion of this activity, participants should be able to:
 Recognize why the use of second-generation antihistamines is recommended over older generation ones.
 Assess when antihistamines may be appropriate for use in the management of allergic asthma anaphylaxis.
 Evaluate the use of antihistamines with and without other therapies in patients with allergic rhinitis and urticaria depending on disease
severity.
Release Date: October 1, 2023
Expiration Date: September 30, 2025
Target Audience
Physicians involved in providing patient care in the field of allergy/asthma/immunology.
Accreditation
The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.
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The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA
Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure Statement
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Asthma and Immunology (ACAAI) policy, all individuals in a position to control or influence the content of an activity must disclose all
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whose primary business is producing, marketing, selling, re-selling, or distributing health care products used by or on patients. Examples 1
of such organizations include:
 Advertising, marketing, or communication firms whose clients are ineligible companies.
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 Device manufacturers or distributors; diagnostic labs that sell proprietary products.
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The ACCME does not consider providers of clinical service directly to patients to be commercial interests. For more information, visit
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Disclosure in no way implies that the information presented is biased or of lesser quality. It is incumbent upon course participants to be
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Planners:
 Kurt Shulenberger, MA, has no relevant financial relationships with ineligible companies to disclose.
 David Stukus, MD, Consultant: Novartis, ARS Pharmaceuticals.
Authors:
 Sophia Linton, BSc, has no relevant financial relationships with ineligible companies to disclose.
 Lubnaa Hossenbaccus, MSc, has no relevant financial relationships with ineligible companies to disclose.
 Anne K. Ellis, MD, MSc, FRCPC, Advisor: Bausch Health, GlaxoSmithKline, Johnson & Johnson, Novartis, Medexus, Miravo, Pfizer: Speaker:
Novartis, Miravo, Pfizer: Consultant: Bayer LLC.
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CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at [email protected] or 847-427-1200.
414 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420

formation, and cognitive impairment.4,5 They can also block trans- with placebo.14 A meta-analysis of 8 RDBCT trials including a total of
mission through the muscarinic, a-adrenergic, and serotonin recep- 3532 participants assessed the efficacy of fexofenadine in AR using
tors and through ion channels to cause other undesirable adverse adverse events (AEs), TSS, and other individual symptom scores as a
effects (cardiac and other sites).5 First-generation antihistamines also clinical end point. Fexofenadine positively affected all the outcome
inhibit CYP2D6 hepatic enzymes and can potentially alter the metab- measures (P < .001) and found no significant AE compared with
olism of other drugs dependent on CYP2D6 metabolism, such as tri- placebo (P = .75).15 Also, a meta-analysis of 48 studies and 18,014
cyclic antidepressants, some antipsychotics, b-blockers, anti- participants was conducted to assess the potential sedative effects
arrhythmics, and tramadol.6 These first-generation antihistamines of levocetirizine. When compared with placebo, levocetirizine pro-
are no longer recommended by several practice guidelines to treat duced modest sedative effects (relative risk (RR): 1.67; 95% confi-
allergic conditions.7 dence interval [CI], 1.17-2.38), and when compared with first-
Newer generation antihistamines, which first became available generation antihistamines, levocetirizine had fewer sedative effects
in North America in the 1980s, are superior to first-generation and less change of reaction time (mean difference: 250.76 second;
antihistamines because they exhibit high H1 receptor selectivity, 95% CI, 338.53 to 162.98).16 Another systematic review and meta-
low brain permeability, and longer durations of action, and there- analysis compared 51 RCTs with a total of 14,551 participants to
fore are less likely to produce unwanted adverse effects.4 Intrana- assess the safety of fexofenadine. When compared with the second-
sal antihistamines (INAHs), which are also inverse agonists of H1 generation antihistamines, fexofenadine produced significantly mar-
receptors, are classified as second-generation antihistamines. ginal sedative effects (odds ratio (OR), 0.59; 95% CI, 0.38-0.93; P = .02)
They have a faster onset of action (15-30 minutes) compared and significantly less change of most of the cognitive and psychomo-
with oral antihistamines but can sometimes taste bitter and can tor function. It is also worth mentioning that the US Food and Drug
also be found in combination with intranasal corticosteroids Administration (FDA) has classified astemizole, fexofenadine, lorata-
(INCSs).8-10 dine, and terfenadine as nonsedating. Cetirizine is classified as sedat-
This review aims to provide a comprehensive overview of evi- ing.17 More evidence is also accumulating to support the use of
dence-based use of H1 antihistamines for mainly allergic rhinitis (AR) second-generation oral H1 antihistamines in specific patient popula-
while also discussing urticaria, anaphylaxis, and allergic asthma tions, such as children. In 2021, Miligkos et al18 performed a system-
aimed at the practicing physician. atic review of the risk of AEs in second-generation antihistamines in
children below or equal to 12 years old compared with first-genera-
tion antihistamines, montelukast, or placebo. The authors included
45 studies between 1989 and 2017 and remarked that second-gener-
Allergic Rhinitis
ation antihistamines were safer and better tolerated, though, cetiri-
AR is an inflammatory nasal condition present in 1 in 5 Cana- zine was the most sedating among new-generation antihistamines.18
dians.11 As of 2021 in the United States, approximately 1 in 4 (25.7%) High-quality evidence supporting the newer agents, such as bilas-
of adults had “seasonal” AR (SAR).12 The clinical manifestations of AR tine and rupatadine, is also accumulating. A RDBCT phase 2 study
—sneezing, nasal obstruction, and mucus discharge—are caused by was performed comparing the effects of bilastine with cetirizine, fex-
allergen exposure in sensitized atopic individuals and an immuno- ofenadine, and placebo on TNSS after grass exposure in the Vienna
logic cascade mediated by IgE. This cascade can be separated into the Challenge Chamber. There were 75 individuals with SAR who partici-
early stage (occurs within minutes) and late-stage reactions (occurs pated in this study which found that although bilastine and fexofena-
within 4 to 8 hours). dine have similar effects on TNSS during the first 4 hours after
According to Allergic Rhinitis and its Impact on Asthma (ARIA), administration, bilastine and cetirizine were significantly more effec-
the type of AR is classified based on the length and recurrence of the tive than fexofenadine between 22 and 26 hours after administra-
symptom manifestations. Intermittent AR (IAR) is characterized by tion.19 Another large RDBCT was conducted to compare the efficacy
symptoms for less than 4 days per week or less than 4 consecutive and safety of bilastine and cetirizine after 14 days of treatment. This
weeks. Persistent AR (PER) is characterized by symptoms occurring study included 683 SAR participants and used the area under curve
more than 4 days per week for at least 4 consecutive weeks.13 AR can (AUC) of TSS (TSS-AUC) and individual symptom scores as clinical
also be classified into SAR and “perennial” AR (PAR), referring to outcomes. The reduction in TSS-AUC was similar between bilastine
symptoms occurring in conjunction with specific allergy seasons or and cetirizine, and both were significantly greater than placebo
year-round. Both classifications are used in the literature; however, (P < .001). However, the symptoms of somnolence (P < .001) and
IAR and PER are not synonymous with SAR and PAR. fatigue (P < .02) were significantly greater among patients in the
Several guidelines and position papers have published treatment cetirizine-treated group compared with the bilastine-treated
recommendations for AR while taking into consideration pregnancy group.20 A similar study was conducted on 650 PAR participants,
categories (Table 1). As found in Table 1, the use of second-generation except the treatment regimen lasted 4 weeks. Still, the mean AUC of
H1 antihistamines is strongly recommended in favor of older, more reflective total 6-symptom scores compared with baseline was signif-
sedating first-generation antihistamines as first-line treatment for icantly reduced in both groups compared with placebo (P < .05).21
AR. INAHs and combinations of INAHs and INCSs are recommended Finally, a 2013 systematic review and meta-analysis of RDBCTs
for moderate-to-severe AR. This section of the review will summarize assessed the efficacy and safety of rupatadine for AR. The authors
recent and notable high-quality studies published on these 3 types of included 10 trials involving 2573 patients and reported a favorable
pharmaceuticals. risk-benefit ratio for rupatadine in treating AR considering AEs, TSS,
TNSS, and individual nasal and ocular symptom scores.22
Second-Generation Antihistamines
Patient-focused decisions should be the priority when prescribing
Large trials and subsequent meta-analyses have established the a specific oral H1 antihistamine. Recent systematic reviews and meta-
safety and efficacy of newer generation H1 antihistamines. In 2007, a analyses evaluating multiple oral H1 antihistamines have noted intra-
meta-analysis of randomized, double-blind, controlled trials (RDBCT) class differences which may affect a treatment recommendation. A
was performed to assess the efficacy of desloratadine in the treat- meta-analysis reviewed data from 92,900 AR patients enrolled in 9
ment of AR. A total of 13 studies and 3108 participants were included open-label, prospective, observational studies. Four different anti-
in this meta-analysis. Desloratadine was associated with significant histamines were compared in this meta-analysis—desloratadine,
reductions in total symptom score (TSS) (P = .004), total nasal symp- ebastine, fexofenadine, and levocetirizine—using TSS and TNSS as
tom score (TNSS) (P < .001), and nasal blockage (P = .005), compared clinical end points. Compared with the other antihistamines as a
 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420 415

Table 1
Recent Guidelines and Position Papers on AR Treatment6,7,13,57-59

Guideline/position paper Title Year published Recommendation

ARIA ARIA guidelines—2016 revision 2016 - In patients with SAR, a combination of an INCS with an oral antihista-
mine or an INCS alone is suggested.
- In patients with PAR, an INCS alone rather than a combination of an
INCS with an oral antihistamine is suggested.
- In patients with SAR, a combination of an INCS with an INAH or an
INCS alone is suggested.
- In patients with PAR, either a combination of an INCS with an INAH or
an INCS alone is suggested.
- In patients with SAR, a combination of an INCS with an INAH rather
than an INAH alone is suggested.
CSACI CSACI position statement: Newer generation H1 2019 - Newer generation antihistamines should be preferred over first-gen-
antihistamines are safer than first-generation eration antihistamines for the treatment of allergic rhinoconjunctivi-
H1 antihistamines and should be the first-line tis and urticaria.
antihistamines for the treatment of allergic rhi-
nitis and urticaria
GA2LEN Risk of first-generation H1 antihistamines: a 2010 - Older first-generation H1 antihistamines should no longer be avail-
GA2LEN position paper able over the counter as prescription-free drugs for self-medication of
allergic and other diseases now that newer second-generation nonse-
dating H1 antihistamines with superior risk/benefit ratios are widely
available at competitive prices.
AAO-HNSF Clinical Practice Guideline: Allergic Rhinitis 2015 - Clinicians should recommend oral second-generation/less sedating
antihistamines for patients with AR and primary complaints of sneez-
ing and itching.
AAAAI/ACAAI Allergy Rhinitis 2020: a practice parameter update - Recommend against prescribing a first-generation antihistamine and
Practice Parameters are in favor of a second-generation antihistamine when prescribing
an oral antihistamine for the treatment of AR.
- We recommend that the clinician offer INAH as an initial treatment
option for patients with SAR.
ICAR International consensus statement on allergy and 2023 - Newer-generation oral antihistamines can be considered in the treat-
rhinology: allergic rhinitis—2023 ment of AR.
- Intranasal antihistamines may be used as first- or second-line therapy
in the treatment of AR.
- Current evidence is mixed to support antihistamines as an additive
therapy to INCS, as several randomized trials have not revealed a ben-
efit over INCS alone for symptoms of AR.
- Combination therapy with INCS and intranasal antihistamine may be
used as second-line therapy in the treatment of AR when initial
monotherapy with either INCS or antihistamine does not provide
adequate control.

Abbreviations: AAAAI, American Academy of Allergy Asthma & Immunology; AAO-HNSF, American Academy of Otolaryngology—Head and Neck Surgery; ACAAI, American College
of Allergy Asthma and Immunology; AR, allergic rhinitis; ARIA, Allergic Rhinitis and Its Impact on Asthma; CSACI, Canadian Society of Allergy and Clinical Immunology; GA2LEN,
Global Allergy and Asthma European Network; ICAR, International Consensus Statement on Allergy and Rhinology; INAH, intranasal antihistamine; INCS, intranasal corticosteroid;
PAR, perennial allergic rhinitis; SAR, seasonal allergic rhinitis.

subgroup, levocetirizine significantly improved symptom scores supporting the benefits of azelastine compared with placebo.29,30
especially in patients with severe AR.23 The same group performed a Perhaps more relevant is that several large trials have been published
meta-analysis on 7 RDBCTs (total of 1603 participants) to compare comparing the pharmacokinetics and efficacy of azelastine with other
€ sges et al24 found that
the efficacy of levocetirizine and loratadine. Mo drug classes including oral antihistamines and INCSs. Patel et al8 ran-
levocetirizine was significantly more effective than loratadine in domized SAR participants to treatment with azelastine nasal spray
improving the TSS (P < .01). (n = 150), mometasone nasal spray (n = 150), or placebo (n = 150)
In summary, there are large amounts of high-quality data sup- during an 8-hour exposure to ragweed pollen in the environmental
porting the use of second-generation oral antihistamines as the cor- exposure chamber. They found that azelastine nasal spray signifi-
nerstone of AR management. cantly improved TNSS at 15 minutes compared with placebo
(P < .001) and that azelastine was significantly more effective than
mometasone at each time point (P ≤ .001).8 A different RDBCT com-
Intranasal Antihistamines
pared intranasal azelastine with intranasal fluticasone propionate in
Levocabastine hydrochloride nasal spray is the only monotherapy 610 SAR patients over 14 days. Overall, the reduction in reflective-
INAH currently available in Canada. In the United States, there are 2 TNSS (rTNSS) from baseline from both treatment groups was similar
INAHs available, olopatadine and azelastine hydrochloride sprays. (P = .20), and there was also comparable improvement in reflective
The systemic bioavailability of these intranasal antihistamines ranges total ocular symptom score (TOSS, P = .24) and reflective total of 7
from 40% to 80%.25-27 In 2021, the FDA approved azelastine hydro- symptom scores (P = .78). Notably, there was not a clinically or statis-
chloride as an over-the-counter formulation, making INAHs available tically significant difference between azelastine and fluticasone pro-
for the first time without a prescription.28 This change may improve pionate for reduction in the Rhinoconjunctivitis Quality of Life
access to this medication as a treatment option for AR. Questionnaire.31 A smaller study exposed 46 participants to the
There is a paucity of large studies featuring novel INAHs in the last Vienna Challenge Chamber for 6 hours to compare the onset of action
decade. There is however significant evidence in the literature and efficacy of azelastine nasal spray and desloratadine tablets. Single
416 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420

doses of study medication were administered 2 hours after the start MP29-02, including large RDBCTs from Carr et al37 (n = 3398) and Kli-
of the allergen challenge. Azelastine nasal spray was significantly mek et al38,39 (n = 1781 and n = 2988). Still, there is limited evidence
more effective compared with desloratadine tablets (P = .005) and comparing MP29-02 or MP-AzeFlu or even free combinations of aze-
placebo (P < .001), and the onset of action was 15 minutes for azelas- lastine and fluticasone propionate with other drug combinations.
tine compared with 150 minutes for desloratadine.9 Overall, these One such study by LaForce et al40 compared olopatadine hydrochlo-
studies provide evidence that azelastine is comparable if not more ride nasal spray in combination with fluticasone propionate (OLO/FP)
efficacious than other drug classes. with azelastine hydrochloride nasal spray in combination with fluti-
A small number of studies conducted head-to-head comparisons casone propionate (AZE/FP). This RDBCT included 150 participants
of INAHs with regard to efficacy, sensory attributes, and tolerability whereby 75 participants were randomized to OLO/FP and AZE/FP,
to reveal how they compare to each other overall. The largest trial respectively. Although both groups had statistically significant
compared olopatadine hydrochloride nasal spray 0.6% relative to aze- improvements over baseline in rTNSS (P < .05), there were no signifi-
lastine hydrochloride nasal spray 0.1% and an inactive vehicle in the cant differences between either group in mean change from baseline
treatment of SAR. This phase III multicenter study consisted of 544 in rTNSS over the 2-week treatment period (P = .80) or the mean per-
participants who received treatment for 16 days. The mean reduc- cent reduction from baseline in rTNSS (P = .37).40 Bousquet et al41
tions from baseline in rTNSS were 26.8%, 29.9%, and 18.4% with olo- compared MP29-02 to a different AH-INCS drug combination, specifi-
patadine, azelastine, and inactive vehicle, respectively (P = .003). cally oral loratadine and intranasal fluticasone propionate (LORA/FP)
Olopatadine and azelastine were similarly well tolerated, except for in a single-center, RDBCT using an allergen environmental exposure
prevalence and intensity of bitter taste, which were significantly chamber. A total of 78 participants completed the study which found
lower with olopatadine (P = .05 and P = .005, respectively).32 The sen- that TNSS was significantly reduced vs placebo from 5 minutes for
sory attributes of these 2 INAHs were also compared by Meltzer MP-AzeFlu and 150 minutes for LORA/FP onward (both P < .05) until
et al33 in 100 participants. Similarly, they saw 60.6% of the patients the end of assessment (0-4 hours). Interestingly, there was no statis-
favored olopatadine, 30.3% favored azelastine, and 9.2% indicated no tically significant difference between LORA/FP and placebo over the
preference. Specifically, olopatadine was superior to azelastine in entire assessment interval (P = .18).41
terms of immediate taste post dose, overall aftertaste, overall patient The evidence provided here supports the use of single combina-
preference, and likelihood of use.33 Finally, there was a multicenter tion products, such as MP-AzeFlu, for the treatment of AR instead of
RDBCT of azelastine nasal spray 0.1% vs levocabastine nasal spray free-combination therapy of AH/INCS. However, health care utiliza-
0.05% in 244 participants with AR for 14 consecutive days. There tion and costs for patients should also be considered by prescribers.
were no significant differences between the 2 treatment groups in In 2016, Harrow et al42 performed a resource utilization and cost
terms of TNSS, total effective rate, and onset of action. However, comparison between MP-AzeFlu and the alternative concomitant use
higher symptom relief rates were found in the levocabastine nasal of INAHs with INCSs by assessing the retrospective administrative
spray group than the azelastine nasal spray group within 30 minutes claims over a 1-year period in the United States. All-cause−related
of administering the first dose.34 pharmacy fills and pharmacy, medical, and total costs were signifi-
cantly reduced by using MP-AzeFlu (n = 810) instead of the free com-
bination of drugs (n = 726). For AR-related health care resource
Intranasal Antihistamine/Intranasal Corticosteroid Combinations
utilization, the MP-AzeFlu cohort had significantly fewer pharmacy
Monotherapy with H1 antihistamines or INCSs is recommended fills than the free-combination cohort (P < .001) with no significant
for AR by the many guidelines outlined in Table 1. For patients who difference in outpatient services and specialist visits (P = .14 and
are unresponsive to monotherapy, combination therapy with H1 anti- P = .12, respectively). Six-month AR-related pharmacy and total costs
histamines and INCSs (AH-INCS) is frequently prescribed and recom- were significantly lower (P < .001 and P = .001) for the MP-AzeFlu
mended for patients with moderate-to-severe AR. cohort than the free-combination cohort. There was no statistically
Evidence to support the effectiveness of AH-INCS combination significant difference in AR-related medical costs between the 2
therapy in AR can be found in systemic reviews and meta-analyses. cohorts (P = .45).42
In 2018, Seresirikachorn et al35 analyzed 16 studies consisting of
4026 participants to determine the effects of AH-INCS for treating AR.
Urticaria
Compared with INCS, AH-INCS significantly decreased TNSS (P <
.001; n = 3348) and TOSS (P = .003; n = 2378). In a subgroup analysis, Urticaria is an inflammatory dermatologic disease characterized
the authors found that the combination therapy with intranasal AH- by wheals with surrounding angioedema (flares) that can be catego-
INCS was significantly superior to INCS alone (P < .001; n = 1998) but rized as acute or chronic, based on duration of symptoms. If symp-
not significant for oral AH-INCS (P = .35; n = 1350). However, there toms persist longer than 6 weeks, the urticaria is considered to be
was also no significant difference between these intranasal AH-INCS chronic. Chronic urticaria can be further classified as being inducible
and oral AH-INCS (P = .07). With regard to disease-specific quality of with a definite trigger, or spontaneous if a trigger is not definitely
life, there were no significant differences (P = .12; n = 1981) between identifiable.
combination AH-INCS and INCS alone.35 Another meta-analysis was There is strong evidence-based consensus (Table 2) that second-
interested in the direct head-to-head comparison of oral AH-INCS vs generation H1 antihistamines should be used as first-line therapy of
intranasal AH-INCS in AR. In 2020, Du et al36 analyzed 13 publications urticaria on a regular basis.43 A double-blind trial found 20 mg of
with a total of 5066 participants. Their pooled results revealed no sig- bilastine to be equivalent in terms of tolerability to 5 mg of levocetiri-
nificant difference in TNSS between oral AH-INCS and INCS alone zine; however, the latter had significantly less (P = .04) sedative
(n = 909, P for overall effect = .28; P for heterogeneity = .76). In con- adverse effects and was more effective at reducing urticaria symp-
trast, intranasal AH-INCS was found to be superior to INCS in improv- toms.44 Levocetirizine had better efficacy when compared with rupa-
ing TNSS (n = 4157, P for overall effect < .01, P for heterogeneity = tadine, which is also a safe and effective nonsedating second-
.38).36 Overall, these articles suggest that intranasal AH-INCS has generation H1 antihistamine.45,46 First-generation antihistamines are
benefit over INCS on nasal and ocular symptom improvement for strongly not recommended due to their sedative and potentially seri-
treating AR, but oral AH-INCS is not recommended. ous adverse effects. Patients who are unresponsive to the standard
MP29-02 is a fixed-dose nasal spray combination that contains dosing of second-generation H1 antihistamines can receive up to, but
azelastine hydrochloride and fluticasone propionate, which is also not surpassing, a 4-fold increase in dosage as second-line treat-
called MP-AzeFlu. There is strong evidence to support the efficacy of ment.47 There is a growing body of evidence to support the efficacy
 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420 417

Table 2
Guidelines for the Management of Urticaria Related to Antihistamines39

The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria 2021
Recommendations for:
- Second-generation H1 antihistamine to be used as first-line treatment for all types of urticaria
- Updosing of a second-generation H1 antihistamine up to 4-fold in patients with chronic urticaria unresponsive to a standard-dosed second-generation H1 antihistamines as sec-
ond-line treatment before considering other treatments
- Second-generation H1 antihistamines taken regularly for the treatment of patients with chronic urticaria
- Adding on omalizumab for the treatment of patients with chronic urticaria unresponsive to high-dose second-generation H1 antihistamines
- Using cyclosporine for the treatment of patients with chronic urticaria unresponsive to high dose of second-generation H1 antihistamine and omalizumab
Recommendations against:
- Using different H1 antihistamines at the same time
- Using higher than 4-fold standard-dosed H1 antihistamines in chronic urticaria
No recommendations:
- The combined use of H1 and H2 antihistamines in patients with chronic urticaria

Abbreviations: APAAACI, Asia Pacific Association of Allergy, Asthma and Clinical Immunology; EAACI, European Academy of Allergology and Clinical Immunology; EuroGuiDerm,
European Dermatology Forum; GA2LEN, Global Allergy and Asthma European Network.

and safety of high-dose antihistamines for CSU including a systemic combination therapy with second-generation oral H1 antihistamines
review and meta-analysis of 7 studies that evaluated the efficacy and is superior to oral treatment alone.58,59 There are also dual-acting
safety of high-dose second-generation H1 antihistamines. It was antihistamine and mast cell-stabilizing molecules such as azelastine,
found that treatment with high-dose second-generation H1 antihist- epinastine, ketotifen, and olopatadine, which have immediate anti-
amines was associated with a significantly higher response rate than histaminic effects and longer-lasting mast cell stabilization activity.
standard dose (risk ratio, 1.13; 95% CI, 1.02-1.26; P = .02). Conversely, Evidence from head-to-head studies comparing these compounds
high doses also were associated with significantly higher somnolence reveals that differences exist in their spectrum of activity and patient
rates than standard dose (risk difference (RD), 0.05; 95% CI, 0.01- preference and comfort.60-64
0.09; P = .02). There was no significant difference in AEs between
standard- and high-dose treatments.48 The same treatment recom-
mendations apply to children and pregnant or lactating women, after Anaphylaxis
patient-specific considerations, such as weight-adjusted dosing and
Anaphylaxis is an acute, systemic, and potentially fatal response
risk-benefit assessments, respectively.43 It should be noted that older
to a trigger that involves 2 or more bodily systems. There is an up to
populations may be particularly susceptible to the sedative action of
2% chance of one experiencing an anaphylactic episode throughout
some H1 antihistamines, when recommended doses are exceeded.49
their lifetime.65 Anaphylaxis is most frequently IgE mediated,
Similarly, it might also cause risks in some older patients with renal,
whereby the triggering allergen binds to IgE on cells, which triggers
hepatic, and/or cardiac disorders.50
an inflammatory cascade resulting in the release of histamine and
For those who remain unresponsive to high doses of H1 antihist-
other mediators. This manifests clinically as hypotension, bronchodi-
amines, add-on therapies include omalizumab (anti-IgE biologic) and
lation, vasoconstriction, dyspnea, angioedema, and edema, because
cyclosporine (a calcineurin inhibitor) as third- and fourth-line
of the systemic effects of histamine. Importantly, epinephrine is
options, respectively.51,52 In early 2023, a phase 3 trial evaluated the
unequivocally first-line therapy for anaphylaxis.66 Adjunctive treat-
efficacy and safety of dupilumab in CSU patients aged above or equal
ment, considered second- or third-line therapies, includes antihist-
to 6 years who remained symptomatic despite treatment with H1
amines. These are primarily used for the management of
antihistamines. Efficacy end points included the Urticaria Activity
dermatologic symptoms, such as pruritus and urticaria, which can
Score over 7 days (UAS7) and the Dermatology Life Quality Index
occur with anaphylaxis; however, it is important that they do not
(DLQI). UAS7 improved significantly in dupilumab-treated patients;
delay the readministration of epinephrine if needed. Although hista-
at week 24, least squares (LS) mean change from baseline was 20.5/
mine is involved in the mechanistic pathways of anaphylaxis, anti-
12.0 (difference 8.5; P = .001) for dupilumab/placebo, respectively.
histamines do not relieve especially the more critical symptoms of
DLQI scores improved significantly in dupilumab-treated patients; at
hypotension and airway construction. Antihistamines are not as rap-
week 24, LS mean change from baseline was 10.8/7.6 (difference
idly acting as epinephrine, taking hours compared with minutes, so
3.2; nominal P = .003) for dupilumab/placebo, respectively.53 More
they can be rather harmful if used as a first-line option in the case of
recently, trials evaluating Bruton tyrosine kinase inhibitors, such as
life-threatening circumstances as is anaphylaxis.67 In fact, the 2020
remibrutinib and fenebrutinib, in combination with H1 antihist-
practice parameter guidelines (Table 3) for anaphylaxis recommends
amines have also reported good efficacy and safety profiles.54,55
against the use of antihistamines as a preventative method for pre-
venting biphasic anaphylaxis; no clear benefits were observed from
using H1 antihistamines. The guidelines recommend the preemptive
Allergic Conjunctivitis administration of antihistamines to prevent hypersensitivity reac-
tions to some chemotherapy and rush immunotherapy protocols, but
The EAACI Ocular Allergy Interest Group on Diagnosis and Man-
not when administering radiocontrast media that previously caused
agement of Ocular Allergy classifies allergic conjunctivitis as a sub-
a reaction. Although antihistamines are not a key player in the man-
type of ocular allergies that are mediated by IgE, which include
agement of anaphylaxis, they can be used to address secondary
seasonal (SAC) and perennial allergic conjunctivitis (PAC).56 Accord-
symptoms to provide patients with greater comfort.
ing to ARIA, SAC affects 3% to 42% of the population (depending on
different climatic conditions and age groups), with PAC affecting 1%
to 18%. For patients with allergic conjunctivitis, topical second-gener-
Allergic Asthma
ation H1 antihistamines, levocabastine and emedastine, are recom-
mended instead of the first-generation agents, pheniramine and Allergic asthma is the inflammation of the lower respiratory tract,
antazoline.57 For patients also experiencing nasal symptoms, including the airways and lungs, after exposure to aeroallergens,
418 S. Linton et al. / Ann Allergy Asthma Immunol 131 (2023) 412−420

Table 3
Guidelines for Anaphylaxis Management Related to Antihistamines49

Anaphylaxis—a 2020 practice parameter update, systematic review, and GRADE analysis 2020
Recommendations for:
- Administering glucocorticoids with or without antihistamines to prevent anaphylaxis or infusion-related reactions when indicated for specific agents in chemotherapy
protocols.
- Administering glucocorticoids and/or antihistamines as an intervention to prevent anaphylaxis in patients undergoing aeroallergen rush immunotherapy.
Recommendations against:
- Administering glucocorticoids or antihistamines as an intervention to prevent biphasic anaphylaxis.
- Routinely administering glucocorticoids and/or antihistamines to prevent anaphylaxis in patients with previous radiocontrast hypersensitivity reactions when readministration
of a radiocontrast media agent is required.
No recommendations:
- N/A

Abbreviations: GRADE, Grading of Recommendations, Assessment, Development and Evaluation; N/A, not available.

which affects 60% of patients with asthma. Symptoms of dyspnea, Therapeutics, Bayer LLC, Ora Inc, and Regeneron in the past. The other
coughing, wheeze, and chest tightness are the clinical outcomes of a authors declare that they have no competing interests.
mast cell-mediated immune response after allergen exposure, where
histamine is released and results in bronchoconstriction and mucous
secretion. Despite having a role in the immunologic pathways, H1 Funding
antihistamines are not typically even considered in the treatment The authors have no funding sources to report.
algorithm for allergic asthma.68 Inhaled corticosteroids are first-line
therapy and enable rapid bronchodilation of the respiratory airways.
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