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The efficacy of intranasal antihistamines in the treatment of allergic rhinitis
The efficacy of intranasal antihistamines in the treatment of allergic rhinitis Michael A. Kaliner, MD*; William E. Berger, MD†; Paul H. Ratner, MD‡; and Charles J. Siegel, MD§
Objectives: To discuss the new use of intranasal antihistamines as first-line therapies, compare and contrast this class of medication with the traditionally available medications, and discuss the potential for intranasal antihistamines to provide relief superior to second-generation oral antihistamines. Data Sources: Review articles and original research articles were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. Study Selection: Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. Results: This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in numerous randomized, placebo-controlled trials to be more efficacious than the oral antihistamines. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, multiple studies have shown an equal effect of the 2 classes of medication. Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, some intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. Conclusions: The future of allergy treatment will likely involve a combination of both intranasal corticosteroids and intranasal antihistamines because of the benefits of local administration and their additive effect on efficacy. Ann Allergy Asthma Immunol. 2011;106:S6 –S11. INTRODUCTION A symposium that investigated defining the role of intranasal antihistamines for allergic rhinitis led to the organization of the National Jewish Health Symposium entitled Rethinking the Treatment of Allergic Rhinitis; The Role of Intranasal Antihistamines: “Me Too Drugs” or a Novel Class?, held in Denver, Colorado, on October 8, 2009. This article discusses the efficacy of intranasal and oral antihistamines and how Affiliations: * Institute for Asthma and Allergy, Chevy Chase and Wheaton, Maryland, and George Washington University School of Medicine, Washington, DC; † Southern California Research, Mission Viejo, California; ‡ Sylvana Research Associates, San Antonio, Texas; § University of Missouri, Kansas City and Gladstone, Missouri. Disclosures: Dr Kaliner has served as a consultant or on an advisory board for Alcon, GlaxoSmithKline, Greer, Novartis/Genentech, SanofiAventis, Merck-Schering, Sepracor, and Teva; has served on a speakers’ bureau for Alcon, Novartis/Genentech, Sepracor, and Teva; and has received research grants from all asthma and allergy companies. Dr Berger has served as a consultant, speaker, and/or on an advisory board for Alco, AsraZeneca, Sanofi-Aventis, Novartis, Meda, Sepracor, GSK, Schering Plough, Genentech, Altana, Dey, Verus, Apieron, Map, and Teva. Dr Ratner has served as a consultant to Meda, Alcon and Sepracor Pharmaceuticals. Dr Siegel has served as a speaker for Merck, Teva, Meda, AstraZeneca, and Sanofi-Aventis and has served as a consultant for Meda. Funding Sources: This consensus panel received a grant from Meda Pharmaceuticals to explore the role of intranasal antihistamines in the treatment of allergic rhinitis. Received for publication May 10, 2010; Received in revised form July 30, 2010; Accepted for publication August 15, 2010. © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.anai.2010.08.010
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they compare with other leading therapies. Review articles and original research were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. Although antihistamines have been in use for more than 60 years and topical therapies of the respiratory tract have been used for centuries, it is only recently that intranasal antihistamines have begun to be more widely used as a treatment for allergic rhinitis. Intranasal antihistamine effects have been shown on many mediators (eg, histamines, leukotrienes, cytokines, chemokines, mast cells, eosinophils, and neutrophils) at clinically relevant concentrations, whereas much higher concentrations (than routine dosing) of oral antihistamines are required to achieve any anti-inflammatory effects. This local delivery with its unique pharmacologic profile may be the reason that intranasal antihistamines are so effective at relieving symptoms of allergic rhinitis.1 As stated in another article in this supplement, the newest recommendations regarding the use of intranasal antihistamines include the following: (1) they may be considered for first-line treatment for allergic and nonallergic rhinitis; (2) they may be more beneficial because of their rapid onset of action; (3) they are efficacious and equal to or superior to oral second-generation antihistamines for the treatment of sea-
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sonal allergic rhinitis (SAR); (4) they have been associated with a clinically significant beneficial effect on nasal congestion; (5) they are generally less effective than intranasal corticosteroids, although current US studies show equal efficacy; and (6) they may provide added benefit for mixed-type rhinitis when used as combined therapy.2 Other benefits of these drugs not outlined in the guidelines include the ability to achieve higher concentrations of active drug directly to the target tissue, as well as minimizing adverse effects seen with systemic medications.3 Evidence supporting these claims is presented herein. EFFICACY OF INTRANASAL ANTIHISTAMINES There are currently 2 intranasal histamine1 antihistamines on the market that have been approved by the Food and Drug Administration (FDA): azelastine hydrochloride (original approval as Astelin in 1996; approval as Astepro in 2008) (Fig 1) and olopatadine hydrochloride (approval as Patanase in 2008) (Fig 2). Astelin is approved by the FDA for the treatment of SAR (ⱖ5 years) and for the treatment of symptoms of nonallergic vasomotor rhinitis (ⱖ12 years).4 Astepro is approved by the FDA for the relief of symptoms of SAR and perennial allergic rhinitis (ⱖ12 years).5 Patanase is approved by the FDA for the relief of symptoms of SAR (ⱖ6 years).6,7 Table 1 lists the currently marketed and FDAapproved intranasal antihistamines and their doses. The efficacy of intranasal antihistamines is measured many different ways in the literature and FDA-approval packages, including the change in the total nasal symptom score (TNSS), individual symptom scores, onset of action, quality of life, ocular symptom scores, comparison with other antihistamines (intranasal and oral) or intranasal corticosteroids, and any advantages of add-on therapy (such as enhanced efficacy). Two key end points for the trials discussed in this publication include the TNSS and the quality-of-life score. The most common subjective score used is the TNSS. The TNSS is a compilation of 4 individual symptoms: runny nose/ rhinorrhea, itchy nose, sneezing, and nasal congestion/obstruction. Each of these symptoms is measured on a 4-point (0 –3) rating scale. The reflective TNSS (rTNSS) is typically calculated as the average of daytime and nighttime TNSSs evaluated during 12-hour intervals. The quality-of-life scale used in many of the studies is the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), developed by Elizabeth Juniper. The RQLQ is a disease-specific, validated quality-of-life
Figure 1. Azelastine hydrochloride.
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Figure 2. Olopatadine hydrochloride.
questionnaire that has been developed to evaluate functional problems that are troublesome to adults with rhinoconjunctivitis. The RQLQ evaluates 7 domains using a 7-point (0 – 6) rating scale. These domains include daily activities, sleep, nonnose and noneye symptoms, emotions, practical problems, nasal symptoms, and eye symptoms.8 Azelastine Hydrochloride With Saline-Based Vehicle The original double-blind, controlled trial for FDA approval for azelastine (Astelin, 137 g per spray) involved 251 patients with symptomatic SAR randomized to treatment with azelastine (2 sprays per nostril either once or twice daily) or placebo for 2 weeks. The total symptom complex (runny nose, itchy nose, sneezing, nose blows, watery eyes, postnasal drip, cough, and itchy eyes, ear, throat, and palate) showed statistically significant improvement for azelastine over placebo (placebo, 7% improvement; azelastine once daily, 20% improvement; azelastine twice daily, 27% improvement; both P ⱕ .05). In addition, the major symptom complex (runny nose, itchy nose, sneezing, nose blows, and watery eyes) showed statistically significant improvement for azelastine given twice daily over placebo (placebo, 7% improvement; azelastine twice daily; 30% improvement; P ⱕ .05). There were no safety concerns.9 Azelastine has a rapid onset of action, within 15 minutes. Four hundred fifty patients were exposed to ragweed pollen in an environmental chamber and then randomized to azelastine, mometasone, or placebo nasal spray. Azelastine showed a significant improvement in TNSS over placebo at 15 minutes, with the improvement remaining consistent during the 8 hours of the study.10 Mometesone had no effects during this time frame. Azelastine Hydrochloride With Sucralose and Sorbitol A second formulation of azelastine in a new vehicle of sucralose and sorbitol (0.1% or 0.15% Astepro) was approved by the FDA at 137 g per spray (0.1%) in 2008 and 205.5 g per spray (0.15%) in 2009. The reformulated azelastine (Astepro) was developed to address some of the common adverse effects experienced with the original azelastine (Astelin) formulation that could have a negative effect on compliance and treatment effect. A comparative 2-week trial of the different azelastine formulations randomized 850 SAR patients to 6 treatment groups. The treatment groups com-
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Table 1. FDA-Approved, Currently Marketed Intranasal Antihistamines and Doses Product
Dose for adults with SAR
Dose for adults with VMR
Azelastine hydrochloride (Astelin)
1–2 sprays per nostril twice daily (137, 274, or 548 g/d) 1–2 sprays per nostril twice daily (548 g/d) 2 sprays per nostril daily (411 g/d) 2 sprays per nostril twice daily (2,660 g/d)
2 sprays per nostril twice daily (548 g/d)
0.1% Azelastine hydrochloride (Astepro) 0.15% Azelastine hydrochloride (Astepro) Olopatadine hydrochloride
Dose for adults with PAR
2 sprays per nostril twice daily (822 g/d)
Abbreviations: FDA, Food and Drug Administration; SAR, season allergic rhinitis; PAR, perennial allergic rhinitis; VMR, vasomotor rhinitis.
pared the original azelastine formulation, the reformulated azelastine (0.1%), and placebo nasal sprays at both 1 and 2 sprays per nostril twice daily. Original azelastine nasal spray and the reformulated 0.1% azelastine spray produced comparable improvements in the TNSSs at both doses and a clear dose-response difference between the 1- and 2-spray doses. Reformulated 0.1% azelastine (2 sprays per nostril twice daily) demonstrated a significant decrease in rTNSSs (P ⬍ .001) over placebo. In addition, the incidence of bitter taste was 6% with 0.1% azelastine, 10% with azelastine at 1 spray per nostril, 7% with 0.1% azelastine, and 8% with azelastine at 2 sprays per nostril.5,11 The safety and efficacy of 0.15% azelastine in treating SAR were evaluated in 5 randomized, multicenter, double-blind, placebo-controlled clinical trials in a total of 2,499 patients. Two 2-week studies compared 0.15% azelastine at 2 sprays per nostril twice daily to 0.1% azelastine, azelastine, and/or placebo, and three 2-week trials compared 0.15% azelastine at 2 sprays per nostril once daily to placebo. The 0.15% azelastine consistently demonstrated a statistically significant greater decrease in rTNSS than placebo at the end of 2 weeks.5 The 0.15% Azelastine administered once daily was studied in patients with SAR exposed to Texas mountain cedar. After a week taking placebo, potential patients were assessed for eligibility; a 12-hour rTNSS (morning or evening) of at least 8 on 3 individual symptoms was required, as well as a 12-hour reflective nasal congestion score of 2 or 3 on 3 separate assessments (1 of which needed to be within 2 days of day 1). Five hundred thirty-six patients were randomized in a 1:1 ratio to receive 2 sprays per nostril once daily of either 0.15% azelastine or placebo for a 2-week period. After 14 days, the percentage improvement in the 12-hour rTNSS was significant (P ⬍ .001) for 0.15% azelastine (19%) compared with placebo (10%). Changes from baseline in 12-hour reflective individual nasal symptom scores (eg, nasal congestion, runny nose, itchy nose, and sneezing) were also found to be significant (P ⬍ .01 for all) for azelastine vs placebo. The 0.15% azelastine had a higher report of bitter taste (4.5%) and nasal discomfort (4.5%), but all other adverse events were similar to placebo.12 Olopatadine Hydrochloride The first multicenter, randomized, double-blind, placebocontrolled study trial designed to study the safety and efficacy
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of olopatadine hydrochloride nasal spray (Patanase, 665 g per spray) was performed during a 2-week treatment period for SAR. Five hundred sixty-five patients (12– 80 years old) were randomized to receive 2 sprays per nostril, twice daily, of 0.4% olopatadine, 0.6% olopatadine, or placebo. Both doses of olopatadine were statistically significant to placebo for percentage change from baseline in overall reflective (P ⫽ .004 and P ⬍ .001, respectively) and instantaneous (P ⫽ .02 and P ⫽ .003, respectively) assessments of TNSS. The 0.6% olopatadine dose was statistically significant to placebo for reducing a number of reflective and instantaneous individual assessments (sneezing, runny nose, itchy nose, itchy eyes), instantaneous assessments of watery eyes, and the overall and each of the 7 individual domain scores of the RQLQ. There were no safety issues.13 The second reported multicenter, randomized, doubleblind, placebo-controlled study trial designed to study the safety and efficacy of olopatadine nasal spray was performed during a 2-week period for the treatment of SAR to mountain cedar. Six hundred seventy-seven patients (12– 81 years old) were randomized to receive 2 sprays per nostril, twice daily, of 0.4% olopatadine, 0.6% olopatadine, or placebo. Both doses of olopatadine were statistically significantly better when compared with placebo for percentage change from baseline in overall reflective and instantaneous assessments of TNSS. The 0.6% olopatadine dose was statistically significantly better than placebo for reducing a number of reflective and instantaneous individual assessments (eg, sneezing, runny nose, itchy nose, stuffy nose, itchy eyes, and watery eyes). There were no safety issues.14 In addition, a comparative, multicenter, double-blind, randomized, crossover study compared the sensory attributes of olopatadine (0.6%) vs the original formulation of azelastine in 110 patients with SAR or perennial allergic rhinitis. Patients received each treatment separately with a washout between exposures and evaluated their sensory perceptions immediately and 45 minutes after dosing. Patients also evaluated their overall perceptions of the 2 medications after administering both therapies. Olopatadine was superior to azelastine in overall patient preference (62.4% vs 33.9%; P ⫽ .0001), aftertaste (60.6% vs 30.3%; P ⫽ .0005), and likelihood of extended use (60.9% vs 34.5%; P ⫽ .0004). Perceptions of additional attributes after administration of both
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treatments were significant and favored olopatadine (P ⱕ .0036 for all variables).15 Intranasal Antihistamine Compared With Oral Antihistamine Therapy Intranasal antihistamines have been found in some studies to be as or more effective than oral antihistamines, with fewer adverse effects. LaForce and colleagues found that azelastine improved symptoms in a 2-week study of 335 SAR patients who remained symptomatic after 1 week of treatment with fexofenadine and were randomized to 1 of 3 treatment groups: (1) azelastine, 2 sprays per nostril twice daily, plus placebo capsules twice daily; (2) azelastine, 2 sprays per nostril twice daily, plus fexofenadine, 60 mg twice daily; or (3) placebo, 2 sprays per nostril twice daily, plus placebo capsules twice daily. After 2 weeks of treatment, both the azelastine group (P ⫽ .007) and the azelastine and fexofenadine capsules group (P ⫽ .003) were found to significantly improve the change from baseline to day 14 in TNSS (eg, runny nose, sneezing, itchy nose, and nasal congestion) vs placebo. Patients treated with azelastine nasal spray alone and the combination of azelastine nasal spray and fexofenadine had a 19% improvement in TNSS compared with 11% with placebo. The design of this study represents the real world— patients seeking physician care for their rhinitis symptoms; these patients have likely tried other prescription or over-thecounter medications and experienced an inadequate response. The results suggest that azelastine is effective when fexofenadine does not fully relieve symptoms and is an effective monotherapy for patients with SAR because no additional therapeutic benefit vs placebo was observed by adding fexofenadine to azelastine vs azelastine alone. The significant improvement in the TNSS of patients with SAR supports the use of azelastine as a first-line option in the treatment of SAR.16 A second study comparing azelastine with oral loratadine had similar findings. Four hundred forty patients with SAR who remained symptomatic after 1 week of treatment with loratadine were randomized to 1 of 4 treatment groups: (1) azelastine, 2 sprays per nostril twice daily, plus 1 placebo capsule daily; (2) azelastine, 2 sprays per nostril twice daily, plus a 10-mg capsule of loratadine daily; (3) placebo, 2 sprays per nostril twice daily, and a 5-mg capsule of desloratadine once daily; or (4) placebo, 2 sprays per nostril twice daily, and 1 placebo capsule daily. After 2 weeks of treatment, the azelastine (P ⬍ .001), azelastine and loratadine (P ⬍ .001), and desloratadine (P ⫽ .039) groups were found to significantly improve the change from baseline to day 14 in TNSS (eg, runny nose, sneezing, itchy nose, and nasal congestion) vs placebo. Patients treated with azelastine alone and azelastine plus loratadine each had a 22% improvement in TNSS compared with 11% with placebo; a 17.5% improvement was seen with desloratadine (approximately 40% less than for azelastine groups). This trial indicates that azelastine is effective for SAR patients when loratadine does not fully relieve symptoms and is an effective alternative to
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switching to another oral antihistamine or to using multiple antihistamines in the treatment of rhinitis symptoms. These results additionally suggest that azelastine is an effective antihistamine that should be considered as a first-line treatment option for rhinitis patients, especially when oral antihistamines have been inadequate.17 In both the loratadine and fexofenadine studies, bitter taste was the most frequently reported adverse event with azelastine. The incidence of somnolence in all active treatment arms was similar to that seen with placebo. The incidences of bitter taste (11%–13%), somnolence (1%–2%), and headache (0%–3%) reported in both studies were lower than those in the product insert (in SAR, 19.7%, 11.5%, and 14.8%, respectively) (Meda Pharmaceuticals, unpublished data, Fall 2004).16,17 There were 2 separate studies (Azelastine Cetirizine Trial [ACT] 1 and 2) that compared the effectiveness and quality of life of azelastine (nasal spray) with cetirizine (oral tablets) in patients with moderate-to-severe seasonal allergic rhinitis.18,19 In ACT 1 and ACT 2, 152 and 179 patients received azelastine, 2 sprays per nostril twice daily, plus placebo tablets, and 155 and 175 patients received 10-mg tablets of cetirizine once daily plus placebo nasal spray for a 2-week period, respectively. Patients continued to complete their morning and evening TNSS diaries during the 14-day treatment period. In addition, on days 1 and 14, patients completed the RQLQ. Investigators found a significant change in TNSS for azelastine compared with cetirizine patients in both ACT 1 (29.3% vs 23.0%, P ⫽ .015) and ACT 2 (23.9% vs 19.6%, P ⬍ .001). In ACT 1, as the study progressed over time, azelastine produced numerically greater improvements on each day compared with cetirizine and showed statistical superiority over cetirizine beginning on day 8 through day 14 (P ⬍ .05) (nonsignificant difference over cetirizine on day 11). In ACT 2, azelastine produced numerically greater improvements on each day compared with cetirizine and showed statistical superiority over cetirizine on day 6 (P ⬍ .05). Quality of life was measured at day 1 and day 14 in patients at least 18 years of age using the RQLQ. Both treatment groups in ACT 1 and ACT 2 showed significant improvements in the overall RQLQ score from baseline (P ⬍ .001). Significant differences were noted for azelastine over cetirizine in both ACT 1 and ACT 2 in the overall RQLQ score (P ⫽ .049 and P ⫽ .002, respectively). Azelastine was associated with a 27% improvement in quality-of-life measures in ACT 1 and a 36% improvement in ACT 2 compared with patients receiving cetirizine. Significant differences were also noted in favor of azelastine for the each of the individual domain scores (P ⱕ .05) in ACT 2 but not in ACT 1. In both ACT trials, azelastine was well tolerated. The most common adverse events in patients receiving azelastine were bitter taste, headache, epistaxis, and somnolence. All other adverse events occurred at an incidence less than 1%.
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Intranasal Antihistamine Compared With Nasal Corticosteroids A frequently cited meta-analysis in this category is by Yanez and Rodrigo.20 The conclusions the authors reached from this meta-analysis include that nasal corticosteroids produce greater relief than intranasal antihistamines. However, this meta-analysis is not ideal for US practical use because most studies were performed in Europe with the average dose of intranasal antihistamines lower than the recommended dose in the United States. This panel believes that additional studies in this area at the doses of antihistamines used in the United States are imperative to determine the comparative efficacy of these 2 classes of drugs. MedPointe Pharmaceuticals (now Meda Pharmaceuticals) performed a pilot study of azelastine nasal spray vs fluticasone nasal spray vs cetirizine oral capsules. Patients were qualified to enter the lead-in period with a minimum 12-hour rTNSS of 8 of a possible 12 and were given a 1-week supply of placebo nasal spray and placebo capsules. After 1 week of treatment, 60 patients with less than 25% to 33% improvement (TNSS ⱖ6) were randomized to 1 of 4 treatment arms: (1) azelastine, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15); (2) azelastine, 2 sprays per nostril twice daily, and cetirizine in capsules (n ⫽ 15); (3) fluticasone, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15); and (4) placebo, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15). Azelastine was statistically superior to fluticasone and placebo at every time point beginning at 30 minutes and up to 210 minutes (P ⬍ .05); fluticasone was not statistically significant vs placebo during this same period (Meda Pharmaceuticals Inc, unpublished data, Fall 2004). Azelastine was statistically superior to all treatment groups 24 hours after initial administration (P ⬍ .05) but not after 7 days of administration. Olopatadine was also compared with fluticasone in a study by Kaliner and colleagues. One hundred thirty patients were randomized to 2 sprays per nostril per day for a 2-week treatment of SAR with olopatadine (0.6%) or fluticasone (50 g). Both of the treatments significantly reduced both reflective and instantaneous assessments of nasal and ocular symptoms during the 2-week study (P ⬍ .05) and were safe and well tolerated. Both olopatadine and fluticasone nasal sprays reduced SAR symptoms (ocular and nasal) by the same amount, with the only significant difference being that olopatadine provided a greater and faster onset of action.21 Onset of Action for Intranasal Antihistamines Compared With Nasal Corticosteroids Two studies were performed to compare the onset of action for intranasal antihistamines compared with that for mometasone nasal spray. Earlier placebo-controlled studies were conducted in outdoor parks with smaller numbers of patients.22,23 Initial assessments were made 1 hour after administration of study drugs and at hourly intervals thereafter. The onset of action for these earlier studies for azelastine was
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determined to be within 2 to 3 hours; subsequent clinical experience suggests an even shorter onset of action. Patients with SAR (allergic to ragweed) were exposed to ragweed pollen in an environmental exposure unit. After 2 to 4 priming visits, a TNSS had to be 6 to 12 for randomization. Four hundred fifty patients were randomized to azelastine, mometasone, or placebo nasal sprays. Azelastine has a rapid onset of relief within 15 to 45 minutes and significantly reduced the TNSS from baseline at 15 minutes after initial administration of study drug compared with placebo and mometasone (P ⬍ .001 for each). This significant difference in TNSS persisted over time throughout the 8-hour study period for azelastine compared with placebo and mometasone.10 Patel and colleagues performed a second study in the environmental exposure unit, this time comparing the onset of action of olopatadine with mometasone in SAR patients. Patients (ⱖ18 years) with fall SAR (N ⫽ 425) were “primed” by exposure to ragweed allergen and then randomized to receive olopatadine (n ⫽ 142), mometasone (n ⫽ 142), or placebo (n ⫽ 141) given as 2 sprays per nostril once in the morning. The primary end point was TNSS evaluated during 12 hours after treatment. A statistically significant improvement in TNSS with olopatadine nasal spray was evident at the first posttreatment measurement (30 minutes, P ⬍ .05) compared with placebo and at the second posttreatment measurement (60 minutes, P ⬍ .05) compared with mometasone nasal spray. Olopatadine was better than placebo at reducing TNSS within 30 minutes of dosing and remained superior for at least 12 hours (P ⬍ .05). Mometasone showed no change from placebo until 150 minutes (P ⬍ .05) after dosing and even then showed a smaller effect than olopatadine.24 These 2 studies show the much shorter onset of action for intranasal antihistamines over other oral medications for allergic rhinitis. Intranasal Antihistamine Combined With Nasal Corticosteroids A study was recently performed by Ratner and colleagues to determine whether an intranasal antihistamine could provide added clinical benefit to an intranasal corticosteroid in patients with more severe allergic rhinitis symptoms. A total of 151 patients with fall SAR who were experiencing moderate to severe symptoms at the time of study received fluticasone, 2 sprays per nostril once daily; azelastine, 2 sprays per nostril twice daily; or the combination for 2 weeks. TNSS improved 27.1% with fluticasone, 24.8% with azelastine, and 37.9% with the combination (P ⬍ .05 vs either agent alone). A similar and statistically significant benefit in terms of nasal congestion was also observed (P ⫽ .042 vs. fluticasone and P ⫽ .016 vs. azelastine). All treatments provided sustained symptom improvement throughout the 14-day study period and were well tolerated.25 CONCLUSION This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in multiple
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randomized, placebo-controlled trials to be significantly more efficacious than the oral antihistamines in short-term studies. Studies using nasal antihistamines for longer periods would be useful. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, some studies have shown an equal effect of the 2 classes of medication.26 Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. These comparison studies are all short term, and longer examinations might be useful. The future of allergy treatment will likely involve a combination of the 2 types of intranasal medications because research has shown they have an additive effect on efficacy.27 ACKNOWLEDGMENTS We thank Meda Pharmaceuticals for providing the funding for this research; National Jewish Health for hosting the panel and coordinating publication efforts; Dr Deborah Wilkerson for her assistance in writing this article; and Mary E. King, PhD, for editorial assistance.
13. 14.
15. 16.
17. 18.
19.
20.
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25.
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jects with seasonal allergic rhinitis. Allergy Asthma Proc. 2009;30: 512–518. Meltzer EO, Hampel FC, Ratner PH, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:600 – 606. Ratner PH, Hampel FC, Amar NJ, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis to mountain cedar. Ann Allergy Asthma Immunol. 2005;95: 474 – 479. Meltzer EO, Garadi R, Laforce C, et al. Comparative study of sensory attributes of two antihistamine nasal sprays: olopatadine 0.6% and azelastine 0.1%. Allergy Asthma Proc. 2008;29:659 – 668. LaForce CF, Corren J, Wheeler WJ, Berger WE; Rhinitis Study Group. Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine. Ann Allergy Asthma Immunol. 2004;93:154 –159. Berger WE, White MV; Rhinitis Study Group. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann Allergy Asthma Immunol. 2003;91:205–211. Corren J, Storms W, Bernstein J, Berger W, Nayak A, Sacks H; Azelastine Cetirizine Trial No. 1 (ACT 1) Study Group. Effectiveness of azelastine nasal spray compared with oral cetirizine in patients with seasonal allergic rhinitis. Clin Ther. 2005;27:543–553. Berger W, Hampel F Jr, Bernstein J, Shah S, Sacks H, Meltzer EO. Impact of azelastine nasal spray on symptoms and quality of life compared with cetirizine oral tablets in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2006;97:375–381. Yáñez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2002;89: 479 – 484. Kaliner MA, Storms W, Tilles S, et al. Comparison of olopatadine 0.6% nasal spray versus fluticasone propionate 50 microg in the treatment of seasonal allergic rhinitis. Allergy Asthma Proc. 2009;30:255–262. Weiler JM, Meltzer EO, Benson PM, Weiler K, Widlitz MD, Freitag J. A dose-ranging study of the efficacy and safety of azelastine nasal spray in the treatment of seasonal allergic rhinitis with an acute model. J Allergy Clin Immunol. 1994;94(6 pt 1):972–980. Meltzer EO, Weiler JM, Dockhorn RJ, Widlitz MD, Freitag JJ. Azelastine nasal spray in the management of seasonal allergic rhinitis. Ann Allergy. 1994;72:354 –359. Patel D, Garadi R, Brubaker M, et al. Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28:592–599. Ratner, PH, Hampel F, Van Bavel J, et al. Combination therapy with azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in the treatment of patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2008;100:74 – 81. Kaliner MA. Azelastine and olopatadine in the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. 2009;103:373– 80. Kaliner MA. A novel and effective approach to treating rhinitis with nasal antihistamines. Ann Allergy Asthma Immunol. 2007;99:383–392, 418.
Requests for reprints should be addressed to: Office of Professional Education National Jewish Health 1400 Jackson Street Denver, CO 80206, USA E-mail: [email protected]
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Objectives: To discuss the new use of intranasal antihistamines as first-line therapies, compare and contrast this class of medication with the traditionally available medications, and discuss the potential for intranasal antihistamines to provide relief superior to second-generation oral antihistamines. Data Sources: Review articles and original research articles were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. Study Selection: Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. Results: This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in numerous randomized, placebo-controlled trials to be more efficacious than the oral antihistamines. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, multiple studies have shown an equal effect of the 2 classes of medication. Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, some intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. Conclusions: The future of allergy treatment will likely involve a combination of both intranasal corticosteroids and intranasal antihistamines because of the benefits of local administration and their additive effect on efficacy. Ann Allergy Asthma Immunol. 2011;106:S6 –S11. INTRODUCTION A symposium that investigated defining the role of intranasal antihistamines for allergic rhinitis led to the organization of the National Jewish Health Symposium entitled Rethinking the Treatment of Allergic Rhinitis; The Role of Intranasal Antihistamines: “Me Too Drugs” or a Novel Class?, held in Denver, Colorado, on October 8, 2009. This article discusses the efficacy of intranasal and oral antihistamines and how Affiliations: * Institute for Asthma and Allergy, Chevy Chase and Wheaton, Maryland, and George Washington University School of Medicine, Washington, DC; † Southern California Research, Mission Viejo, California; ‡ Sylvana Research Associates, San Antonio, Texas; § University of Missouri, Kansas City and Gladstone, Missouri. Disclosures: Dr Kaliner has served as a consultant or on an advisory board for Alcon, GlaxoSmithKline, Greer, Novartis/Genentech, SanofiAventis, Merck-Schering, Sepracor, and Teva; has served on a speakers’ bureau for Alcon, Novartis/Genentech, Sepracor, and Teva; and has received research grants from all asthma and allergy companies. Dr Berger has served as a consultant, speaker, and/or on an advisory board for Alco, AsraZeneca, Sanofi-Aventis, Novartis, Meda, Sepracor, GSK, Schering Plough, Genentech, Altana, Dey, Verus, Apieron, Map, and Teva. Dr Ratner has served as a consultant to Meda, Alcon and Sepracor Pharmaceuticals. Dr Siegel has served as a speaker for Merck, Teva, Meda, AstraZeneca, and Sanofi-Aventis and has served as a consultant for Meda. Funding Sources: This consensus panel received a grant from Meda Pharmaceuticals to explore the role of intranasal antihistamines in the treatment of allergic rhinitis. Received for publication May 10, 2010; Received in revised form July 30, 2010; Accepted for publication August 15, 2010. © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.anai.2010.08.010
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they compare with other leading therapies. Review articles and original research were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. Although antihistamines have been in use for more than 60 years and topical therapies of the respiratory tract have been used for centuries, it is only recently that intranasal antihistamines have begun to be more widely used as a treatment for allergic rhinitis. Intranasal antihistamine effects have been shown on many mediators (eg, histamines, leukotrienes, cytokines, chemokines, mast cells, eosinophils, and neutrophils) at clinically relevant concentrations, whereas much higher concentrations (than routine dosing) of oral antihistamines are required to achieve any anti-inflammatory effects. This local delivery with its unique pharmacologic profile may be the reason that intranasal antihistamines are so effective at relieving symptoms of allergic rhinitis.1 As stated in another article in this supplement, the newest recommendations regarding the use of intranasal antihistamines include the following: (1) they may be considered for first-line treatment for allergic and nonallergic rhinitis; (2) they may be more beneficial because of their rapid onset of action; (3) they are efficacious and equal to or superior to oral second-generation antihistamines for the treatment of sea-
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sonal allergic rhinitis (SAR); (4) they have been associated with a clinically significant beneficial effect on nasal congestion; (5) they are generally less effective than intranasal corticosteroids, although current US studies show equal efficacy; and (6) they may provide added benefit for mixed-type rhinitis when used as combined therapy.2 Other benefits of these drugs not outlined in the guidelines include the ability to achieve higher concentrations of active drug directly to the target tissue, as well as minimizing adverse effects seen with systemic medications.3 Evidence supporting these claims is presented herein. EFFICACY OF INTRANASAL ANTIHISTAMINES There are currently 2 intranasal histamine1 antihistamines on the market that have been approved by the Food and Drug Administration (FDA): azelastine hydrochloride (original approval as Astelin in 1996; approval as Astepro in 2008) (Fig 1) and olopatadine hydrochloride (approval as Patanase in 2008) (Fig 2). Astelin is approved by the FDA for the treatment of SAR (ⱖ5 years) and for the treatment of symptoms of nonallergic vasomotor rhinitis (ⱖ12 years).4 Astepro is approved by the FDA for the relief of symptoms of SAR and perennial allergic rhinitis (ⱖ12 years).5 Patanase is approved by the FDA for the relief of symptoms of SAR (ⱖ6 years).6,7 Table 1 lists the currently marketed and FDAapproved intranasal antihistamines and their doses. The efficacy of intranasal antihistamines is measured many different ways in the literature and FDA-approval packages, including the change in the total nasal symptom score (TNSS), individual symptom scores, onset of action, quality of life, ocular symptom scores, comparison with other antihistamines (intranasal and oral) or intranasal corticosteroids, and any advantages of add-on therapy (such as enhanced efficacy). Two key end points for the trials discussed in this publication include the TNSS and the quality-of-life score. The most common subjective score used is the TNSS. The TNSS is a compilation of 4 individual symptoms: runny nose/ rhinorrhea, itchy nose, sneezing, and nasal congestion/obstruction. Each of these symptoms is measured on a 4-point (0 –3) rating scale. The reflective TNSS (rTNSS) is typically calculated as the average of daytime and nighttime TNSSs evaluated during 12-hour intervals. The quality-of-life scale used in many of the studies is the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), developed by Elizabeth Juniper. The RQLQ is a disease-specific, validated quality-of-life
Figure 1. Azelastine hydrochloride.
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Figure 2. Olopatadine hydrochloride.
questionnaire that has been developed to evaluate functional problems that are troublesome to adults with rhinoconjunctivitis. The RQLQ evaluates 7 domains using a 7-point (0 – 6) rating scale. These domains include daily activities, sleep, nonnose and noneye symptoms, emotions, practical problems, nasal symptoms, and eye symptoms.8 Azelastine Hydrochloride With Saline-Based Vehicle The original double-blind, controlled trial for FDA approval for azelastine (Astelin, 137 g per spray) involved 251 patients with symptomatic SAR randomized to treatment with azelastine (2 sprays per nostril either once or twice daily) or placebo for 2 weeks. The total symptom complex (runny nose, itchy nose, sneezing, nose blows, watery eyes, postnasal drip, cough, and itchy eyes, ear, throat, and palate) showed statistically significant improvement for azelastine over placebo (placebo, 7% improvement; azelastine once daily, 20% improvement; azelastine twice daily, 27% improvement; both P ⱕ .05). In addition, the major symptom complex (runny nose, itchy nose, sneezing, nose blows, and watery eyes) showed statistically significant improvement for azelastine given twice daily over placebo (placebo, 7% improvement; azelastine twice daily; 30% improvement; P ⱕ .05). There were no safety concerns.9 Azelastine has a rapid onset of action, within 15 minutes. Four hundred fifty patients were exposed to ragweed pollen in an environmental chamber and then randomized to azelastine, mometasone, or placebo nasal spray. Azelastine showed a significant improvement in TNSS over placebo at 15 minutes, with the improvement remaining consistent during the 8 hours of the study.10 Mometesone had no effects during this time frame. Azelastine Hydrochloride With Sucralose and Sorbitol A second formulation of azelastine in a new vehicle of sucralose and sorbitol (0.1% or 0.15% Astepro) was approved by the FDA at 137 g per spray (0.1%) in 2008 and 205.5 g per spray (0.15%) in 2009. The reformulated azelastine (Astepro) was developed to address some of the common adverse effects experienced with the original azelastine (Astelin) formulation that could have a negative effect on compliance and treatment effect. A comparative 2-week trial of the different azelastine formulations randomized 850 SAR patients to 6 treatment groups. The treatment groups com-
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Table 1. FDA-Approved, Currently Marketed Intranasal Antihistamines and Doses Product
Dose for adults with SAR
Dose for adults with VMR
Azelastine hydrochloride (Astelin)
1–2 sprays per nostril twice daily (137, 274, or 548 g/d) 1–2 sprays per nostril twice daily (548 g/d) 2 sprays per nostril daily (411 g/d) 2 sprays per nostril twice daily (2,660 g/d)
2 sprays per nostril twice daily (548 g/d)
0.1% Azelastine hydrochloride (Astepro) 0.15% Azelastine hydrochloride (Astepro) Olopatadine hydrochloride
Dose for adults with PAR
2 sprays per nostril twice daily (822 g/d)
Abbreviations: FDA, Food and Drug Administration; SAR, season allergic rhinitis; PAR, perennial allergic rhinitis; VMR, vasomotor rhinitis.
pared the original azelastine formulation, the reformulated azelastine (0.1%), and placebo nasal sprays at both 1 and 2 sprays per nostril twice daily. Original azelastine nasal spray and the reformulated 0.1% azelastine spray produced comparable improvements in the TNSSs at both doses and a clear dose-response difference between the 1- and 2-spray doses. Reformulated 0.1% azelastine (2 sprays per nostril twice daily) demonstrated a significant decrease in rTNSSs (P ⬍ .001) over placebo. In addition, the incidence of bitter taste was 6% with 0.1% azelastine, 10% with azelastine at 1 spray per nostril, 7% with 0.1% azelastine, and 8% with azelastine at 2 sprays per nostril.5,11 The safety and efficacy of 0.15% azelastine in treating SAR were evaluated in 5 randomized, multicenter, double-blind, placebo-controlled clinical trials in a total of 2,499 patients. Two 2-week studies compared 0.15% azelastine at 2 sprays per nostril twice daily to 0.1% azelastine, azelastine, and/or placebo, and three 2-week trials compared 0.15% azelastine at 2 sprays per nostril once daily to placebo. The 0.15% azelastine consistently demonstrated a statistically significant greater decrease in rTNSS than placebo at the end of 2 weeks.5 The 0.15% Azelastine administered once daily was studied in patients with SAR exposed to Texas mountain cedar. After a week taking placebo, potential patients were assessed for eligibility; a 12-hour rTNSS (morning or evening) of at least 8 on 3 individual symptoms was required, as well as a 12-hour reflective nasal congestion score of 2 or 3 on 3 separate assessments (1 of which needed to be within 2 days of day 1). Five hundred thirty-six patients were randomized in a 1:1 ratio to receive 2 sprays per nostril once daily of either 0.15% azelastine or placebo for a 2-week period. After 14 days, the percentage improvement in the 12-hour rTNSS was significant (P ⬍ .001) for 0.15% azelastine (19%) compared with placebo (10%). Changes from baseline in 12-hour reflective individual nasal symptom scores (eg, nasal congestion, runny nose, itchy nose, and sneezing) were also found to be significant (P ⬍ .01 for all) for azelastine vs placebo. The 0.15% azelastine had a higher report of bitter taste (4.5%) and nasal discomfort (4.5%), but all other adverse events were similar to placebo.12 Olopatadine Hydrochloride The first multicenter, randomized, double-blind, placebocontrolled study trial designed to study the safety and efficacy
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of olopatadine hydrochloride nasal spray (Patanase, 665 g per spray) was performed during a 2-week treatment period for SAR. Five hundred sixty-five patients (12– 80 years old) were randomized to receive 2 sprays per nostril, twice daily, of 0.4% olopatadine, 0.6% olopatadine, or placebo. Both doses of olopatadine were statistically significant to placebo for percentage change from baseline in overall reflective (P ⫽ .004 and P ⬍ .001, respectively) and instantaneous (P ⫽ .02 and P ⫽ .003, respectively) assessments of TNSS. The 0.6% olopatadine dose was statistically significant to placebo for reducing a number of reflective and instantaneous individual assessments (sneezing, runny nose, itchy nose, itchy eyes), instantaneous assessments of watery eyes, and the overall and each of the 7 individual domain scores of the RQLQ. There were no safety issues.13 The second reported multicenter, randomized, doubleblind, placebo-controlled study trial designed to study the safety and efficacy of olopatadine nasal spray was performed during a 2-week period for the treatment of SAR to mountain cedar. Six hundred seventy-seven patients (12– 81 years old) were randomized to receive 2 sprays per nostril, twice daily, of 0.4% olopatadine, 0.6% olopatadine, or placebo. Both doses of olopatadine were statistically significantly better when compared with placebo for percentage change from baseline in overall reflective and instantaneous assessments of TNSS. The 0.6% olopatadine dose was statistically significantly better than placebo for reducing a number of reflective and instantaneous individual assessments (eg, sneezing, runny nose, itchy nose, stuffy nose, itchy eyes, and watery eyes). There were no safety issues.14 In addition, a comparative, multicenter, double-blind, randomized, crossover study compared the sensory attributes of olopatadine (0.6%) vs the original formulation of azelastine in 110 patients with SAR or perennial allergic rhinitis. Patients received each treatment separately with a washout between exposures and evaluated their sensory perceptions immediately and 45 minutes after dosing. Patients also evaluated their overall perceptions of the 2 medications after administering both therapies. Olopatadine was superior to azelastine in overall patient preference (62.4% vs 33.9%; P ⫽ .0001), aftertaste (60.6% vs 30.3%; P ⫽ .0005), and likelihood of extended use (60.9% vs 34.5%; P ⫽ .0004). Perceptions of additional attributes after administration of both
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treatments were significant and favored olopatadine (P ⱕ .0036 for all variables).15 Intranasal Antihistamine Compared With Oral Antihistamine Therapy Intranasal antihistamines have been found in some studies to be as or more effective than oral antihistamines, with fewer adverse effects. LaForce and colleagues found that azelastine improved symptoms in a 2-week study of 335 SAR patients who remained symptomatic after 1 week of treatment with fexofenadine and were randomized to 1 of 3 treatment groups: (1) azelastine, 2 sprays per nostril twice daily, plus placebo capsules twice daily; (2) azelastine, 2 sprays per nostril twice daily, plus fexofenadine, 60 mg twice daily; or (3) placebo, 2 sprays per nostril twice daily, plus placebo capsules twice daily. After 2 weeks of treatment, both the azelastine group (P ⫽ .007) and the azelastine and fexofenadine capsules group (P ⫽ .003) were found to significantly improve the change from baseline to day 14 in TNSS (eg, runny nose, sneezing, itchy nose, and nasal congestion) vs placebo. Patients treated with azelastine nasal spray alone and the combination of azelastine nasal spray and fexofenadine had a 19% improvement in TNSS compared with 11% with placebo. The design of this study represents the real world— patients seeking physician care for their rhinitis symptoms; these patients have likely tried other prescription or over-thecounter medications and experienced an inadequate response. The results suggest that azelastine is effective when fexofenadine does not fully relieve symptoms and is an effective monotherapy for patients with SAR because no additional therapeutic benefit vs placebo was observed by adding fexofenadine to azelastine vs azelastine alone. The significant improvement in the TNSS of patients with SAR supports the use of azelastine as a first-line option in the treatment of SAR.16 A second study comparing azelastine with oral loratadine had similar findings. Four hundred forty patients with SAR who remained symptomatic after 1 week of treatment with loratadine were randomized to 1 of 4 treatment groups: (1) azelastine, 2 sprays per nostril twice daily, plus 1 placebo capsule daily; (2) azelastine, 2 sprays per nostril twice daily, plus a 10-mg capsule of loratadine daily; (3) placebo, 2 sprays per nostril twice daily, and a 5-mg capsule of desloratadine once daily; or (4) placebo, 2 sprays per nostril twice daily, and 1 placebo capsule daily. After 2 weeks of treatment, the azelastine (P ⬍ .001), azelastine and loratadine (P ⬍ .001), and desloratadine (P ⫽ .039) groups were found to significantly improve the change from baseline to day 14 in TNSS (eg, runny nose, sneezing, itchy nose, and nasal congestion) vs placebo. Patients treated with azelastine alone and azelastine plus loratadine each had a 22% improvement in TNSS compared with 11% with placebo; a 17.5% improvement was seen with desloratadine (approximately 40% less than for azelastine groups). This trial indicates that azelastine is effective for SAR patients when loratadine does not fully relieve symptoms and is an effective alternative to
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switching to another oral antihistamine or to using multiple antihistamines in the treatment of rhinitis symptoms. These results additionally suggest that azelastine is an effective antihistamine that should be considered as a first-line treatment option for rhinitis patients, especially when oral antihistamines have been inadequate.17 In both the loratadine and fexofenadine studies, bitter taste was the most frequently reported adverse event with azelastine. The incidence of somnolence in all active treatment arms was similar to that seen with placebo. The incidences of bitter taste (11%–13%), somnolence (1%–2%), and headache (0%–3%) reported in both studies were lower than those in the product insert (in SAR, 19.7%, 11.5%, and 14.8%, respectively) (Meda Pharmaceuticals, unpublished data, Fall 2004).16,17 There were 2 separate studies (Azelastine Cetirizine Trial [ACT] 1 and 2) that compared the effectiveness and quality of life of azelastine (nasal spray) with cetirizine (oral tablets) in patients with moderate-to-severe seasonal allergic rhinitis.18,19 In ACT 1 and ACT 2, 152 and 179 patients received azelastine, 2 sprays per nostril twice daily, plus placebo tablets, and 155 and 175 patients received 10-mg tablets of cetirizine once daily plus placebo nasal spray for a 2-week period, respectively. Patients continued to complete their morning and evening TNSS diaries during the 14-day treatment period. In addition, on days 1 and 14, patients completed the RQLQ. Investigators found a significant change in TNSS for azelastine compared with cetirizine patients in both ACT 1 (29.3% vs 23.0%, P ⫽ .015) and ACT 2 (23.9% vs 19.6%, P ⬍ .001). In ACT 1, as the study progressed over time, azelastine produced numerically greater improvements on each day compared with cetirizine and showed statistical superiority over cetirizine beginning on day 8 through day 14 (P ⬍ .05) (nonsignificant difference over cetirizine on day 11). In ACT 2, azelastine produced numerically greater improvements on each day compared with cetirizine and showed statistical superiority over cetirizine on day 6 (P ⬍ .05). Quality of life was measured at day 1 and day 14 in patients at least 18 years of age using the RQLQ. Both treatment groups in ACT 1 and ACT 2 showed significant improvements in the overall RQLQ score from baseline (P ⬍ .001). Significant differences were noted for azelastine over cetirizine in both ACT 1 and ACT 2 in the overall RQLQ score (P ⫽ .049 and P ⫽ .002, respectively). Azelastine was associated with a 27% improvement in quality-of-life measures in ACT 1 and a 36% improvement in ACT 2 compared with patients receiving cetirizine. Significant differences were also noted in favor of azelastine for the each of the individual domain scores (P ⱕ .05) in ACT 2 but not in ACT 1. In both ACT trials, azelastine was well tolerated. The most common adverse events in patients receiving azelastine were bitter taste, headache, epistaxis, and somnolence. All other adverse events occurred at an incidence less than 1%.
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Intranasal Antihistamine Compared With Nasal Corticosteroids A frequently cited meta-analysis in this category is by Yanez and Rodrigo.20 The conclusions the authors reached from this meta-analysis include that nasal corticosteroids produce greater relief than intranasal antihistamines. However, this meta-analysis is not ideal for US practical use because most studies were performed in Europe with the average dose of intranasal antihistamines lower than the recommended dose in the United States. This panel believes that additional studies in this area at the doses of antihistamines used in the United States are imperative to determine the comparative efficacy of these 2 classes of drugs. MedPointe Pharmaceuticals (now Meda Pharmaceuticals) performed a pilot study of azelastine nasal spray vs fluticasone nasal spray vs cetirizine oral capsules. Patients were qualified to enter the lead-in period with a minimum 12-hour rTNSS of 8 of a possible 12 and were given a 1-week supply of placebo nasal spray and placebo capsules. After 1 week of treatment, 60 patients with less than 25% to 33% improvement (TNSS ⱖ6) were randomized to 1 of 4 treatment arms: (1) azelastine, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15); (2) azelastine, 2 sprays per nostril twice daily, and cetirizine in capsules (n ⫽ 15); (3) fluticasone, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15); and (4) placebo, 2 sprays per nostril twice daily, and placebo capsules (n ⫽ 15). Azelastine was statistically superior to fluticasone and placebo at every time point beginning at 30 minutes and up to 210 minutes (P ⬍ .05); fluticasone was not statistically significant vs placebo during this same period (Meda Pharmaceuticals Inc, unpublished data, Fall 2004). Azelastine was statistically superior to all treatment groups 24 hours after initial administration (P ⬍ .05) but not after 7 days of administration. Olopatadine was also compared with fluticasone in a study by Kaliner and colleagues. One hundred thirty patients were randomized to 2 sprays per nostril per day for a 2-week treatment of SAR with olopatadine (0.6%) or fluticasone (50 g). Both of the treatments significantly reduced both reflective and instantaneous assessments of nasal and ocular symptoms during the 2-week study (P ⬍ .05) and were safe and well tolerated. Both olopatadine and fluticasone nasal sprays reduced SAR symptoms (ocular and nasal) by the same amount, with the only significant difference being that olopatadine provided a greater and faster onset of action.21 Onset of Action for Intranasal Antihistamines Compared With Nasal Corticosteroids Two studies were performed to compare the onset of action for intranasal antihistamines compared with that for mometasone nasal spray. Earlier placebo-controlled studies were conducted in outdoor parks with smaller numbers of patients.22,23 Initial assessments were made 1 hour after administration of study drugs and at hourly intervals thereafter. The onset of action for these earlier studies for azelastine was
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determined to be within 2 to 3 hours; subsequent clinical experience suggests an even shorter onset of action. Patients with SAR (allergic to ragweed) were exposed to ragweed pollen in an environmental exposure unit. After 2 to 4 priming visits, a TNSS had to be 6 to 12 for randomization. Four hundred fifty patients were randomized to azelastine, mometasone, or placebo nasal sprays. Azelastine has a rapid onset of relief within 15 to 45 minutes and significantly reduced the TNSS from baseline at 15 minutes after initial administration of study drug compared with placebo and mometasone (P ⬍ .001 for each). This significant difference in TNSS persisted over time throughout the 8-hour study period for azelastine compared with placebo and mometasone.10 Patel and colleagues performed a second study in the environmental exposure unit, this time comparing the onset of action of olopatadine with mometasone in SAR patients. Patients (ⱖ18 years) with fall SAR (N ⫽ 425) were “primed” by exposure to ragweed allergen and then randomized to receive olopatadine (n ⫽ 142), mometasone (n ⫽ 142), or placebo (n ⫽ 141) given as 2 sprays per nostril once in the morning. The primary end point was TNSS evaluated during 12 hours after treatment. A statistically significant improvement in TNSS with olopatadine nasal spray was evident at the first posttreatment measurement (30 minutes, P ⬍ .05) compared with placebo and at the second posttreatment measurement (60 minutes, P ⬍ .05) compared with mometasone nasal spray. Olopatadine was better than placebo at reducing TNSS within 30 minutes of dosing and remained superior for at least 12 hours (P ⬍ .05). Mometasone showed no change from placebo until 150 minutes (P ⬍ .05) after dosing and even then showed a smaller effect than olopatadine.24 These 2 studies show the much shorter onset of action for intranasal antihistamines over other oral medications for allergic rhinitis. Intranasal Antihistamine Combined With Nasal Corticosteroids A study was recently performed by Ratner and colleagues to determine whether an intranasal antihistamine could provide added clinical benefit to an intranasal corticosteroid in patients with more severe allergic rhinitis symptoms. A total of 151 patients with fall SAR who were experiencing moderate to severe symptoms at the time of study received fluticasone, 2 sprays per nostril once daily; azelastine, 2 sprays per nostril twice daily; or the combination for 2 weeks. TNSS improved 27.1% with fluticasone, 24.8% with azelastine, and 37.9% with the combination (P ⬍ .05 vs either agent alone). A similar and statistically significant benefit in terms of nasal congestion was also observed (P ⫽ .042 vs. fluticasone and P ⫽ .016 vs. azelastine). All treatments provided sustained symptom improvement throughout the 14-day study period and were well tolerated.25 CONCLUSION This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in multiple
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randomized, placebo-controlled trials to be significantly more efficacious than the oral antihistamines in short-term studies. Studies using nasal antihistamines for longer periods would be useful. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, some studies have shown an equal effect of the 2 classes of medication.26 Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. These comparison studies are all short term, and longer examinations might be useful. The future of allergy treatment will likely involve a combination of the 2 types of intranasal medications because research has shown they have an additive effect on efficacy.27 ACKNOWLEDGMENTS We thank Meda Pharmaceuticals for providing the funding for this research; National Jewish Health for hosting the panel and coordinating publication efforts; Dr Deborah Wilkerson for her assistance in writing this article; and Mary E. King, PhD, for editorial assistance.
13. 14.
15. 16.
17. 18.
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20.
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