Pharmacotherapy of allergic rhinitis

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2019. | This topic last updated: Apr 08, 2018.

INTRODUCTIONAllergic rhinitis is characterized by paroxysms of sneezing, rhinorrhea, and nasal obstruction and itching of the eyes, nose, and palate. It is also frequently associated with postnasal drip, cough, irritability, and fatigue.

The pharmacologic management of allergic rhinitis is presented in this topic review. The clinical manifestations, diagnosis, differential diagnosis, and pathogenesis of allergic rhinitis are discussed elsewhere. (See «Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis» and «Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis» and «Pathogenesis of allergic rhinitis (rhinosinusitis)».)

OVERVIEWThe management of allergic rhinitis involves the following components:

●Pharmacotherapy, which is discussed in detail in this review.

●Allergen avoidance, which is reviewed separately. (See «Allergen avoidance in the treatment of asthma and allergic rhinitis».)

●Allergen immunotherapy (when appropriate), which is reviewed elsewhere. Immunotherapy may be given as subcutaneous injections or (for a limited number of allergens) as sublingual tablets. Of note, subcutaneous immunotherapy helps prevent the development of asthma in children with allergic rhinitis and thus should be given special consideration in the pediatric population. (See «Subcutaneous immunotherapy for allergic disease: Indications and efficacy» and «Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma».)

Most patients with allergic rhinitis require pharmacotherapy, in addition to allergen avoidance, for satisfactory symptom control. As more medications become available without a prescription, patients can extensively self-treat, although the side effects of some over-the-counter allergy medications, particularly the excessive sedation and anticholinergic effects caused by older antihistamines, can be significant. Therefore, the challenge for clinicians is to assure that patients with moderate-to-severe allergic rhinitis are adequately treated with medications that do not cause undue side effects.

Consensus guidelines have been published for the management of allergic rhinitis [1-12]. The recommendations in this topic review are consistent with these guidelines.

APPROACH TO SPECIFIC PATIENT GROUPSThe management of allergic rhinitis in a specific patient is influenced by the frequency and severity of symptoms, the age of the patient, and the presence of concurrent conditions [2-10]. In this review, an approach to specific patient groups is presented initially, followed by a detailed discussion of available medications. (See ‘Available medications’ below.)

Young children (<2 years of age) — The development of allergic rhinitis requires repeated exposure to inhaled allergens and is therefore uncommon in children under two years of age. If a child under two years appears to have persistent nasal symptoms, other disorders should be considered initially, such as adenoidal hypertrophy or chronic rhinosinusitis. (See «Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis» and «The pediatric physical examination: HEENT», section on ‘Adenoidal hypertrophy’.)

If a young child is determined to have allergic rhinitis after an evaluation for other causes, treatment options include the following:

●Cromolyn sodium nasal spray, one to two sprays three to four times daily, is attractive to some parents and clinicians because it has essentially no adverse effects. However, cromolyn is less effective than glucocorticoid nasal sprays, and the dosing is inconvenient. Despite these limitations, it can be sufficient for controlling mild symptoms. (See ‘Cromolyn sodium’ below.)

●The second-generation antihistamines (cetirizine, loratadine, and fexofenadine) are available in liquid formulations. Cetirizine and fexofenadine are approved for children ≥6 months of age. (See ‘Second- and third-generation antihistamines’ below.)

For children with severe symptoms not responsive to the above measures, a glucocorticoid nasal spray may be administered instead. Mometasone furoate, fluticasone furoate, and triamcinolone acetonide are approved by the US Food and Drug Administration (FDA) for use in children ≥2 years [13,14]. The dose for each of these agents in young children is one spray per nostril once daily. If necessary, two sprays per nostril can be tried for a limited period (we limit to two weeks and reassess symptoms) in view of the age-limited dose approval and the concern for potential systemic side effects (eg, adrenal suppression) in children at the higher dose.

We avoid first-generation antihistamines in young children because these agents can cause paradoxical agitation and may be dangerous in infants [15]. (See ‘First-generation agents’ below.)

Older children and adults — For children over two years of age, the approach to pharmacotherapy is essentially the same as that in adults and depends upon the severity and persistence of symptoms.

Mild or episodic symptoms — Patients with mild or episodic symptoms or episodic symptoms that are related to predictable allergen exposures (visiting a relative’s house with a pet) can be managed with one of the following options:

●A second-generation oral antihistamine administered regularly or as needed (ideally two to five hours before an exposure). Cetirizine (approved for children ≥6 months), loratadine, and fexofenadine (both approved for children ≥2 years) are similarly efficacious and are available in syrups. (See ‘Second- and third-generation antihistamines’ below.)

●An antihistamine nasal spray (eg, azelastine or olopatadine). The FDA has approved the use of azelastine in children >5 years of age and the use of intranasal olopatadine in children >12 years of age (its safety and efficacy have not been evaluated in younger children). (See ‘Antihistamine nasal sprays’below.)

●A glucocorticoid nasal spray (more effective than antihistamines) administered regularly or as needed. For predictable exposures, we suggest initiating therapy two days before, continuing through, and for two days after the end of exposure [16,17]. Mometasone furoate, fluticasone furoate, and triamcinoloneacetonide are approved by the FDA for use in children ≥2 years [13,14].

●Cromolyn nasal spray administered regularly or as needed (ideally 30 minutes before an exposure). Taken in this manner, cromolyn is helpful for brief exposures (minutes to hours). For prolonged exposures, administration should ideally begin four to seven days in advance. Some parents and clinicians prefer to try cromolyn first in children because of its excellent safety profile. (See ‘Cromolyn sodium’ below.)

It should be explained to patients that each of these therapies is more effective when taken regularly, although as-needed use may be sufficient for very mild symptoms.

Persistent or moderate-to-severe symptoms — Glucocorticoid nasal sprays are the most effective pharmacologic therapy for allergic rhinitis and are recommended by guidelines as the best single therapy for patients with persistent or moderate-to-severe symptoms, including seasonal symptoms [1,12]. All of the available preparations are similarly effective, although the newer agents are more convenient and probably safer for long-term use than the older agents. The glucocorticoid nasal sprays with low bioavailability and once daily dosing, such as mometasone furoate and fluticasone furoate, are preferred for use in children. Mometasone and fluticasone furoate are approved by the FDA for use in children ≥2 years [13]. Fluticasone propionate is approved for children ≥4 years. (See ‘Glucocorticoid nasal sprays’ below.)

For patients with moderate-to-severe symptoms and/or in those who fail to respond adequately to initial therapy with glucocorticoid nasal sprays, a second agent can be added. Options include an antihistamine nasal spray, oral antihistamines, cromolyn nasal spray, montelukast, and antihistamine/decongestant combination products. There are few clinical trials directly comparing different combinations of these therapies, and the choice of additional agents should be based upon the patient’s residual symptoms, preferences, and coexistent conditions:

●Combination sprays – Sprays containing both a glucocorticoid and an antihistamine may provide additional benefit over either therapy alone, especially for breakthrough symptoms [18,19]. (See ‘Combination corticosteroid/antihistamine sprays’ below.)

●Addition of a second-generation oral antihistamine – The combination of glucocorticoid nasal sprays and oral antihistamines has not shown clear advantage over glucocorticoid sprays alone in most studies [20,21].

●Addition of a second-generation oral antihistamine/decongestant combination – These provide better symptom-relief than antihistamines alone, although the adverse effects of the decongestant component limit their use in some patients (table 1). (See ‘Oral antihistamine/decongestant combinations’below.)

With concomitant asthma — Up to 40 percent of patients with allergic rhinitis are believed to have concomitant asthma. The leukotriene-modifying agent, montelukast, may be a particularly useful additive therapy for patients with either asthma or nasal polyposis. (See ‘Montelukast’ below.)

With concomitant allergic conjunctivitis — In patients with allergic rhinitis and allergic conjunctivitis, we prefer a combination of a glucocorticoid nasal spray and ophthalmic antihistamine drops, such as epinastine, azelastine, emedastine, or olopatadine, rather than glucocorticoid sprays plus oral antihistamines. A small number of randomized trials have shown the addition of antihistamine eye drops to be more effective and cause less ocular drying than the addition of oral antihistamines [22,23].

Some glucocorticoid nasal sprays (eg, mometasone furoate and fluticasone furoate) have been shown to have a small but statistically significant effect on allergic eye symptoms [24-27]. However, many patients require an additional agent for adequate relief.

Cromolyn sodium is available in ophthalmic preparations and may also be useful as prophylactic therapy before allergen exposures.

Further information about the management of allergic conjunctivitis is found separately. (See «Allergic conjunctivitis: Clinical manifestations and diagnosis».)

Pregnant women — The treatment of allergic rhinitis in pregnant women is reviewed in detail separately. (See «Recognition and management of allergic disease during pregnancy», section on ‘Allergic rhinitis/conjunctivitis’.)

Breastfeeding women — The American Academy of Pediatrics strongly recommends breastfeeding because of the benefits to the neonate and has published a guide for the use of medications during lactation [28]. Another resource is LactMed, an online database of information on medications and lactation hosted by the US National Library of Medicine [29].

Breastfeeding women with very mild allergic rhinitis may not require any medication, although more severe symptoms may warrant treatment.

General guidelines have been proposed (table 2) [30]:

●All patients should practice allergen avoidance. (See «Allergen avoidance in the treatment of asthma and allergic rhinitis».)

●Nasal saline can always be tried for any nonspecific relief it can provide. (See ‘Nasal saline irrigation’ below.)

●Intermittent congestion (symptoms less than four days per week) may be treated judiciously with a topical decongestant spray. (See ‘Nasal decongestant sprays’ below.)

●Mild persistent symptoms (symptoms more than four days/week and more than four weeks/year) may be treated with intranasal budesonide or cromolyn and supplemented by cetirizine or loratadine.

●Moderate-to-severe persistent symptoms may be treated with maintenance intranasal budesonide and/or immunotherapy injections and supplemented as needed with cetirizine or loratadine.

Older adults — Glucocorticoid nasal sprays are the first-line agents for older adults with allergic rhinitis. Second-generation antihistamines can be used safely in some older adult patients, although a few may experience adverse effects, and slowed metabolism may warrant lower starting doses [31]. Antihistamine nasal sprays are also a good option. We avoid first-generation antihistamines in older adults [32]. (See ‘Adverse effects and safety’ below.)

AVAILABLE MEDICATIONSThe most effective single therapy for patients with persistent and significant nasal symptoms is a glucocorticoid nasal spray. Other therapies include oral antihistamines, antihistamine nasal sprays, mast cell stabilizers (the cromoglycates), leukotriene modifiers, and ipratropium. The features and efficacy of the various agents are reviewed in this section.

In contrast, nasal decongestant sprays and systemic glucocorticoids should not be used for routine treatment of allergic rhinitis. (See ‘Therapies requiring caution’below.)

Glucocorticoid nasal sprays — Glucocorticoid nasal sprays are the most effective single maintenance therapy for allergic rhinitis and cause few side effects at the recommended doses [1,12]. These agents are particularly effective in the treatment of nasal congestion. Specific agents include beclomethasone, flunisolide, budesonide, fluticasone propionate, mometasone furoate, fluticasone furoate, and ciclesonide (table 3). Several glucocorticoid nasal sprays are available without a prescription.

Efficacy — Glucocorticoid nasal sprays are more effective than oral antihistamines for relief of nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, and total nasal symptoms, as demonstrated in various randomized trials and a meta-analysis [16,33-37].

Most studies have favored glucocorticoid nasal sprays over antihistamines sprays, as reviewed below. (See ‘Antihistamine nasal sprays’ below.)

Thus, in our opinion, glucocorticoid nasal sprays are the first-line treatment for allergic rhinitis that is significant enough to cause a patient to seek medical advice. Comparative studies among different glucocorticoid nasal sprays have not demonstrated significant differences in efficacy [38,39].

Onset of action — Most glucocorticoid nasal sprays have an onset of action of a few hours [40-42]. However, maximal effect may require several days or weeks in patients with longstanding untreated symptoms.

Mechanisms of action — Glucocorticoids inhibit allergic inflammation in the nose at many levels [43,44]. These agents downregulate inflammatory responses by binding to intracellular glucocorticoid receptors in the cytoplasm of inflammatory cells. The receptors undergo conformational changes upon activation, entering the cell nucleus where they bind with glucocorticoid response elements located on anti-inflammatory genes. These activated genes transcribe messenger RNA for anti-inflammatory proteins. At the same time, activated glucocorticoid receptors suppress the transcription of most cytokine and chemokine genes, whose products promote inflammation. (See «Glucocorticoid effects on the immune system».)

Safety in children and adults — Available glucocorticoid nasal sprays are pharmacologic derivatives of hydrocortisone, in which the molecular structure of the hydrocortisone molecule has been altered to increase potency. First-pass metabolism by the liver decreases drug bioavailability, and the lipophilicity facilitates glucocorticoid penetration into the cell. (See ‘Optimal use’ below.)

Glucocorticoid nasal sprays may be divided into first- and second-generation preparations. These products are equally efficacious, although the total bioavailability (oral and nasal) of second-generation glucocorticoid nasal sprays is markedly lower than that of first-generation agents, resulting in lower risk of systemic effects [45-50]:

●First-generation – Beclomethasone, flunisolide, triamcinolone, and budesonide (10 to 50 percent bioavailability)

●Second-generation – Fluticasone propionate (<2 percent), mometasone furoate (<0.1 percent), ciclesonide (<0.1 percent), and fluticasone furoate (<1 percent)

Local irritation of the nasal mucosa including drying and burning and discomfort from the run-off into the throat of the liquid medication is reported by 2 to 10 percent of patients using sprays [51]. Formulations containing alcohol or propylene glycol are more irritating than aqueous preparations (table 3).

There are two types of nosebleed problems with the use of glucocorticoid nasal sprays, which are frank epistaxis and scant blood found in the nasal mucus:

●The problem of traces of blood in the mucus is often remedied by simply stopping treatment on the side of the nose where blood mucus has been noted for a few days and then restarting therapy. Sometimes patients can minimize these complications by using proper administration technique and by gradually reducing the dose once symptoms are controlled to the lowest effective dose for that individual. It is helpful to demonstrate proper use of all inhaled medications at the time of initial prescription and again at follow-up visits. Aqueous pump and dry powder sprays have different instructions for use. (See ‘Optimal use’ below.)

●Significant epistaxis is reported with both glucocorticoid nasal sprays and placebo in clinical trials and may therefore partly result from mechanical trauma of repeated spraying, although when placebo rates were subtracted, nosebleed was still noted in 2 to 12 percent of patients using different glucocorticoid preparations. Frank epistaxis is often hard to prevent, and once it occurs, it may require future avoidance of glucocorticoid nasal sprays.

●Recurrent or chronic epistaxis, even mild in degree, requires evaluation for chronic nasal inflammation, which can occur in a number of conditions. These include vasomotor rhinitis, chronic nasal staphylococcal infection, Behçet syndrome, granulomatosis with polyangiitis (Wegener granulomatosis), or chronic invasive fungal rhinosinusitis. In our experience, episodic epistaxis also occurs in any dry nose syndrome, such as rhinitis associated with continuous positive airway pressure (CPAP) therapy, sicca syndrome associated with Sjögren syndrome, or atrophic rhinosinusitis. The drying effects of cigarette smoking, caffeinated beverages, and medications with anticholinergic properties can also predispose to bleeding. Recurrent or chronic epistaxis should prompt rhinoscopy to determine the origin of the bleeding, even in patients thought to have epistaxis induced by installation of various medications, since malignancy of the nasal mucosa is also in the differential diagnosis.

Nasal sprays should always be directed away from the septum. There are rare reports of nasal septal perforation with glucocorticoid nasal sprays [52], although long-term studies of large numbers of patients have not found evidence of damage to the nasal mucosa, despite years of use in the majority of patients [53]. A patient education topic on rhinitis, which reviews techniques for optimal use of nasal sprays, is provided separately. (See «Patient education: Allergic rhinitis (Beyond the Basics)».)

The potential for systemic absorption of glucocorticoid nasal sprays, with effects on the hypothalamic-pituitary axis (HPA) and growth in children, has been evaluated in many studies. In a large study of 474 prepubescent children ages 5 to 8.5 years at screening, subjects were randomized to fluticasone furoate or placebo for 52 weeks for the treatment of perennial allergic rhinitis [54]. The dose of active agent was 110 mcg daily, which is the maximum recommended dose for this age group. A statistically significant reduction in growth velocity of -0.27 cm/year (95% CI, -0.48 to -0.06 cm/year) was demonstrated. There was no detectable change in 24-hour urinary cortisol excretion to suggest adrenal suppression. Of note, the protocol used in this study did not allow for dose reduction once symptoms were controlled, which is the desired approach to therapy. Most previous studies, especially those with the second-generation agents, had shown no or limited HPA suppression at recommended doses [55-63]. Taken together, these studies indicate that a small decrement in growth velocity in children is possible with the use of some glucocorticoid nasal sprays, and this side effect needs to be considered in the context of specific glucocorticoids and doses used. Agents that are dosed once daily are preferred in this age group, since these are believed to, although not documented to, be less likely to impact the HPA and growth [47]. (See ‘Optimal use’ below.)

Longer-term studies of the effects on growth caused by inhaled glucocorticoids administered for asthma treatment (which deliver higher doses per actuation) are also reassuring. Despite these reassuring data, the adverse effects of glucocorticoid nasal sprays can be additive with those of other glucocorticoid preparations, such as inhaled agents for concomitant asthma or topical corticosteroids for atopic dermatitis, and therefore, caution is needed [64]. Growth in children should be monitored when any glucocorticoid-containing medication is prescribed. (See «Major side effects of inhaled glucocorticoids», section on ‘Growth deceleration’.)

A small number of studies have examined the effects of glucocorticoid nasal sprays on bone mineral density and intraocular pressure [65-67]. Some studies have demonstrated detrimental effects, although it is unclear whether these are large enough to result in clinically important outcomes over time, such as increased rates of fractures, glaucoma, or cataracts. A practice guideline on rhinitis concluded that studies in both children and adults have failed to demonstrate that these adverse effects are consistent or clinically relevant to use of glucocorticoid nasal sprays [2]. Until more is known, it seems reasonable to inform patients that the risks of these outcomes are likely small, although the impact over a lifetime is not understood.

Glucocorticoid nasal sprays of any type should be tapered to the lowest effective dose in all patients once symptoms are controlled. Conversely, there is no convincing evidence that doses greater than the recommended maximum for each preparation increase efficacy.

Possible drug interactions — Clinically significant adrenal suppression has been reported with the combination of intranasal fluticasone and strong inhibitors of CYP3A4 enzymes (eg, ritonavir, itraconazole, nefazodone) in a small number of case reports [68]. Although it is unclear how frequently this adverse outcome occurs, we suggest that patients receiving treatment with ritonavir or other strong inhibitors of CYP3A4 be treated with a glucocorticoid nasal spray other than fluticasone at the lowest effective dose or that the treating clinician at least be vigilant for signs and symptoms of Cushing syndrome. Budesonide, beclomethasone, triamcinolone, and flunisolide appear to be safer options.

Optimal use — The authors start therapy with the maximal dose for age. Once symptoms are adequately controlled, the dose can be «stepped-down» at one-week intervals to the lowest effective dose. Patients with severe symptoms will require daily use on a chronic basis. Some patients can reduce the use of glucocorticoid nasal sprays gradually and maintain symptom control with every other day or as-needed use. Newer preparations act rapidly (within 3 to 12 hours), and as-needed use appears to be effective [16]. This may be sufficient in patients with episodic symptoms. (See ‘Mild or episodic symptoms’ above.)

Clinicians should become comfortable with several preparations, since each has its advantages and disadvantages relating to added fragrances, taste, and/orirritation.

To optimize the effects of this therapy and compliance with treatment, we suggest the following:

●If mucous crusting is present, patients can rinse the nose with a saline nasal spray or irrigation before the nasal glucocorticoid is applied. Treatment failures can occur if mucus or other debris prevents the medication from coating the nasal mucosa. Saline irrigation is reviewed elsewhere. (See «Chronic nonallergic rhinitis».)

●Preparations with once daily dosing are convenient and can help optimize compliance. All formulations (triamcinolone acetonide, budesonide, fluticasonepropionate, mometasone furoate, ciclesonide, and fluticasone furoate) have a once daily recommended dosing, except for one, flunisolide (which is twice daily).

●With the aqueous (nonaerosol) glucocorticoid nasal sprays, patients should be instructed to keep their head pointed slightly downward during spraying and avoid tilting the head back, as this can cause drainage of the medicine from the nose to the throat. In addition, they should avoid pointing the spray at the septum, which can become irritated. A patient education topic on rhinitis, which reviews techniques for use of nasal sprays, is provided separately. (See «Patient education: Allergic rhinitis (Beyond the Basics)».)

Aerosol formulations — In the United States in 2012, two products became available that use a «dry» aerosol delivery system, beclomethasonedipropionate hydrofluoroalkane (HFA) (Qnasl [brand name]) and ciclesonide HFA (Zetonna [brand name]). These may be more agreeable to patients who dislike the wet run-off or taste side effects that are experienced with some of the aqueous sprays (table 3).

With the aerosol products, patients should be instructed to tilt the head back slightly, dispense the spray, hold the breath for a few seconds, and then exhale through the mouth. The product insert also advises to avoid blowing the nose for 15 minutes after use. The nosepiece should be wiped with a clean, dry tissue weekly, although not cleaned with water.

Combined with decongestant sprays — There may be a role for once daily treatment with the combination of a glucocorticoid nasal spray plus a vasoconstrictor/decongestant spray in adult patients who do not respond optimally to glucocorticoid alone. Combined therapy was evaluated in a randomized trial of 60 adult subjects with perennial allergic rhinitis [69]. Participants were randomly assigned to receive once nightly treatment with fluticasone furoate, oxymetazoline hydrochloride, the combination of both, or placebo. They were monitored for four weeks of therapy and for two weeks post-therapy. Both symptom scores and objective nasal volume (determined with acoustic rhinometry) improved with combination therapy, relative to placebo or oxymetazoline alone. Nasal symptoms were less in the combination group compared with the fluticasone monotherapy group, although nasal volumes were not statistically different. There was no evidence of rhinitis medicamentosa in the combination group. Further study is needed, although we have noted preliminary success in several adult patients in our clinical practice, including some who had reverted to using oral decongestant preparations because glucocorticoid nasal sprays were not providing adequate relief. We attempt to discontinue the vasoconstrictor spray once symptoms are controlled. (See ‘Nasal decongestant sprays’ below.)

Oral antihistamines — Antihistamines typically reduce itching, sneezing, and rhinorrhea, with less impact on nasal congestion, compared with intranasal glucocorticoids. H1 antihistamines are divided into first- and second-generation agents.

Data suggest that H1 antihistamines, by virtue of their ability to downregulate constitutive H1 receptor activity, are not actually receptor antagonists. Rather, they are inverse agonists that shift the equilibrium from the active form of the H1 receptor to the inactive form [70]. Some antihistamines also reduce eosinophil survival [71].

Second- and third-generation antihistamines — The second- and third-generation antihistamines are preferred over first-generation agents because they have similar efficacy and fewer central nervous system effects. Second-generation agents include loratadine, cetirizine, azelastine, and olopatadine. These lipophobic agents were developed primarily to avoid the unwanted anticholinergic and central nervous system effects of the first-generation drugs [72-74]. Onset of action is within one hour for most agents, and peak serum levels are attained in two to three hours [75,76]. They are also longer-acting and are dosed once or twice daily. Like older H1 antihistamines, they have less impact on nasal congestion compared with glucocorticoid nasal sprays. The oral second-generation agents appear to be similarly efficacious to each other [2,77-81].

Metabolites of second-generation antihistamines, such as fexofenadine (the metabolite of terfenadine), desloratadine (the metabolite of loratadine), and levocetirizine (a purified isomer of cetirizine), are sometimes classified as «third-generation antihistamines» [82]. These compounds were designed to have fewer central nervous system effects than the second-generation agents, although whether this is true has not been confirmed [72,83,84].

In experimental models, second- and third-generation antihistamines also have a variety of anti-inflammatory properties, including decreased mast cell mediator release and downregulation of adhesion molecule expression [85]. Inhibition of interleukin-4 (IL-4) and interleukin-13 (IL-13) production may explain reports of their dose-dependent beneficial effect in asthma [86,87].

Role in therapy and efficacy — Second-generation antihistamines are a popular option for many patients, especially those with mild or intermittent symptoms. Patients who experience adverse effects with the second-generation antihistamines (which is rare) or who prefer a local therapy are also better treated with glucocorticoid nasal sprays. We prefer glucocorticoid nasal sprays for patients with chronic or more significant symptoms because of their superior efficacy.

The following general statements can be made concerning the efficacy of second- and third-generation antihistamines:

●Antihistamines are less effective than glucocorticoid nasal sprays, as previously presented [16,34,37]. (See ‘Efficacy’ above.)

●Second-generation antihistamines are equally or more efficacious than cromolyn in relieving symptoms. (See ‘Cromolyn sodium’ below.)

There is no evidence that pharmacologic tolerance develops to antihistamines [88]. In addition, the specific allergic sensitivities a patient has does not impact the antihistamine that is prescribed, although agents are sometimes marketed as effective for perennial or seasonal or indoor or outdoor allergies. This marketing simply reflects the clinical trials that were performed.

There is no evidence that doses of second-generation antihistamines greater than those maximally recommended increase efficacy for allergic rhinitis, with higher than recommended doses being associated with sedation in some cases [89].

Dosing of commonly used agents

●Cetirizine – The standard dose of 10 mg once daily is appropriate for adults and children ages ≥6 years.

The usual dose for children ages 2 to 5 years is 5 mg once daily. Smaller children ages 6 months to 2 years may be given 2.5 mg once daily. The maintenance dose for patients with significant renal and/or hepatic insufficiency should be reduced by one-half.

●Levocetirizine – Levocetirizine is an active enantiomer of cetirizine and produces effects equivalent to cetirizine at about one-half of the dose. For adults and children ≥12 years, the standard dose is 5 mg once daily in the evening. For children ages 6 to 11 years, the standard dose is 2.5 mg once daily in the evening. Levocetirizine is unlikely to be effective as an alternative for patients who acquire tolerance to the effects of cetirizine. Significant dose alteration is necessary in renal insufficiency.

●Loratadine – Loratadine is a long-acting selective H1 antihistamine chemically distinct from cetirizine and has a standard dose of 10 mg once daily for ages ≥6 years.

For children ages 2 to 5 years, the usual dose is 5 mg once daily. For patients with significant renal and/or hepatic insufficiency, the usual dose is administered every other day.

●Desloratadine – Desloratadine is the major active metabolite of loratadine and produces effects equivalent to loratadine at about one-half of the dose. For adults and children ≥12 years, the standard dose is 5 mg once daily.

For children ages 6 to 11 years, the dose is 2.5 mg once daily, and for those ages 1 to 5 years, the dose is 1.25 mg once daily. A lower dose of 1 mg once daily is approved in the United States for small children ages 6 months to 1 year. For patients with significant renal and/or hepatic insufficiency, the usual dose is administered every other day.

●Fexofenadine – The suggested dose of fexofenadine is 180 mg daily for ages ≥12 years or 30 mg twice daily for children ages 2 to 11 years. A lower dose of 15 mg twice daily is approved in the United States for small children ages 6 months to 2 years. For patients with significant renal insufficiency, the adult dose should be reduced to 60 mg once daily. It is best taken without food and specifically not with fruit juices.

Adverse effects — The second-generation antihistamines are less sedating than the first-generation agents, although cetirizine is sedating for approximately 10 percent of patients [90-92]. Loratadine is nonsedating for most adults at the customary dose of 10 mg once daily, although sedation can occur at higher doses [92]. Fexofenadine is nonsedating at recommended doses and even at higher than recommended doses [91,93-95].

●Second-generation antihistamines have varying degrees of anticholinergic effects. Drying of the eyes, in particular, is noticeable to some patients [96].

●Some oral antihistamines may be associated with weight gain, although it is unclear if this is due to stimulation of appetite or reduced activity secondary to sedation and fatigue. Like other central nervous system effects, weight gain is more prominent with the older, first-generation agents, although it can occur in some patients with the second-generation agents [97]. Weight gain would be predicted to be minimal with fexofenadine [98], although we are aware of no studies directly assessing the second-generation agents for this particular untoward effect. Our experience suggests that increased hunger and weight gain with nonsedating antihistamines is minimal to none in most patients.

●St. John’s wort may decrease loratadine and fexofenadine levels, making these antihistamines less effective [99-104]. However, the magnitude and significance of the interaction is uncertain.

First-generation agents — First-generation antihistamines include diphenhydramine, chlorpheniramine, hydroxyzine, brompheniramine, and others. These are available over-the-counter, both as single agents and in combination with other drugs. They are similarly efficacious, compared with each other, with only minor differences [105].

Adverse effects and safety — First-generation antihistamines cause significant sedation because they are lipophilic and easily cross the blood-brain barrier [106]. Central nervous system symptoms are reported by 20 percent or more of patients, and adverse effects on intellectual and motor function are well-documented, even in the absence of subjective awareness of sedation [72,107].

●Impairments affect driving performance and have been implicated in fatal motor vehicle accidents [72,108-111]. First-generation antihistamines are prohibited in many states for some transportation workers (eg, pilots, bus drivers), and individuals taking these agents are considered to be under the influence of drugs [112]. Despite this, a report from the Federal Aviation Administration noted increasing pilot use of these drugs over the past 15 years and reported detection of these agents in 4 and 11 percent of fatalities/accidents in 1990 and 2004, respectively [113]. Other measures of cognitive effects include performance defects on tests of divided attention, working memory, vigilance, and speed [114-116]. Adverse effects are summarized in the table (table 1).

●First-generation antihistamines are problematic in children. In school-aged children, both untreated allergic rhinitis and the use of sedating antihistamines are associated with impaired school performance [108,115,116]. In very young children, first-generation antihistamines can cause paradoxical agitation, and over-the-counter cold remedies containing them have been linked to a small number of deaths in children <2 years of age [15]. (See «The common cold in children: Management and prevention», section on ‘Over-the-counter medications’.)

●First-generation antihistamines may also be problematic in older adults who are more susceptible to their anticholinergic effects, including dry mouth and eyes, urinary hesitancy, and confusion (table 1) [117].

Role in therapy — First-generation antihistamines have a limited role in the treatment of most patients because of their numerous adverse effects. The strategy of combining a second-generation antihistamine during the day and a first-generation antihistamine before bed has been proposed to reduce costs, although it has been shown to cause residual daytime sedation due to the persistence of active metabolites [118,119]. We avoid these medications completely in small children and older adults.

Antihistamine nasal sprays — Azelastine and olopatadine are available as prescription nasal sprays. These agents appear to have some anti-inflammatory effect and can improve nasal congestion [120-122]. They are similarly effective [123,124]. Antihistamine nasal sprays have a rapid onset of action (less than 15 minutes) and can be administered «on demand» [3]. The onset of action is somewhat faster than that of glucocorticoid nasal sprays [41]. However, azelastine has a bitter taste that can be bothersome to some patients (which has been corrected in newer preparations) and was mildly sedating in some of the clinical trials performed in getting the medication on the market, although not in others [125].

Guidelines generally suggest glucocorticoid nasal sprays in preference to antihistamine sprays based upon the fact that the majority of comparison studies favor glucocorticoids [6,126]. In noninferiority trials, both olopatadine and azelastine compared favorably with fluticasone propionate [19,127,128].

Combination corticosteroid/antihistamine sprays — The combination of a topical antihistamine and a topical corticosteroid may be helpful for patients who do not obtain sufficient relief with one agent [129]. In a randomized trial, 3398 patients with moderate-to-severe allergic rhinitis were treated for two weeks with either the combination of azelastine and fluticasone, fluticasone alone, azelastine alone, or placebo, with complete or near-complete resolution of total symptoms in 12, 9, 7, and 4 percent of patients, respectively [18]. A combination spray containing azelastine hydrochloride 137 mcg and fluticasone propionate 50 mcg (Dymista [brand name]) became available in the United States in 2012 and is approved for children older than 12 years and adults. The dose is one actuation per nostril, twice daily.

Oral antihistamine/decongestant combinations — Nonsedating antihistamines combined with the decongestant, pseudoephedrine, provide better symptom relief than antihistamines alone [130]. However, decongestants have a variety of adverse effects, including hypertension, insomnia, irritability, and headache (table 1). There are numerous first-generation antihistamine/decongestant combination products which have been available without a prescription for years. Available second-generation combination agents include loratadine-pseudoephedrine, cetirizine-pseudoephedrine, and fexofenadine-pseudoephedrine.

In the United States, increasing abuse of pseudoephedrine (both as a stimulant in athletics and in the illegal production of methamphetamines) has led to the substitution of phenylephrine for pseudoephedrine in many over-the-counter first-generation combination preparations. However, phenylephrine is less effective for the treatment of rhinitis symptoms and may not be superior to placebo at the 10 mg dose that is commonly available over-the-counter [131,132].

Decongestants are relatively contraindicated in patients with hypertension, contraindicated in those receiving monoamine oxidase inhibitor therapy, and should be used with caution in patients with closed angle glaucoma, cardiovascular or cerebrovascular disease, hyperthyroidism, or bladder neck obstruction.

Cromolyn sodium — Cromolyn sodium is a mast cell stabilizer. It inhibits mast cell release of histamine and other inflammatory mediators by inhibiting the intermediate conductance chloride channel pathways of mast cells, eosinophils, epithelial and endothelial cells, fibroblasts, and sensory neurons [133].

Cromolyn sodium is more effective than placebo in the treatment of seasonal allergic rhinitis. It also has no serious side effects and is available over-the-counter as a nasal spray. However, most studies show it to be less effective than glucocorticoid nasal sprays or second-generation antihistamines [34,35,134].

Cromolyn blocks symptoms associated with the immediate- and late-phase nasal allergen challenge and is effective in doing so, even when used shortly before allergen inhalation. This makes cromolyn particularly useful for individuals who experience episodic symptoms to allergens, such as a cat, where it may be used 30 minutes prior to exposure. For seasonal allergic rhinitis, it is most effective when initiated just prior to the pollen season, rather than after symptoms have begun. Frequent dosing (1 to 2 sprays per nostril four times daily) is required to attain a good effect in seasonal allergic rhinitis. Dose frequency can be reduced after the first two to three weeks of treatment.

In summary, cromolyn sodium is very safe, but its utility is limited by the need for frequent dosing and lower efficacy relative to other agents. It may be tried if other agents are not well-tolerated.

Montelukast — In experimental allergic rhinitis, nasal congestion correlates best with leukotriene C₄ (LTC₄) levels, whereas sneezing and nasal itching correlate with histamine levels. In the United States, there are three antileukotriene agents (montelukast, zafirlukast, zileuton) available for use in asthma, although only montelukast is approved for the management of allergic rhinitis [135-137]. Montelukast is less effective than glucocorticoid nasal sprays for the symptoms of allergic rhinitis, as reviewed previously [138-141]. (See ‘Glucocorticoid nasal sprays’ above.)

Montelukast has been compared with various other therapies or combinations of therapies:

●Montelukast provided relief of symptoms that was similar to loratadine in a systematic review of eight randomized trials [141].

●Montelukast plus a second-generation oral antihistamine (eg, loratadine or fexofenadine) provided more relief than either agent alone in at least two randomized trials [87,142].

●Montelukast plus loratadine provided similar symptom relief as fexofenadine plus pseudoephedrine, although patients receiving the latter combination did not sleep as well, perhaps due to the presence of the decongestant [143].

●Fluticasone propionate nasal spray (200 micrograms per day) was superior to the combination of montelukast and an oral antihistamine in one study, while others found the efficacy of these two approaches comparable [37,141].

Thus, we prefer glucocorticoid nasal sprays over montelukast in any age group with allergic rhinitis. However, the patient who cannot tolerate or refuses nasal sprays may be a candidate for montelukast alone or combined with an antihistamine [144]. In contrast, there are no data to support the addition of montelukast if the combination of glucocorticoid and antihistamine nasal sprays does not bring adequate relief.

Adverse effects — The overall safety profile of leukotriene agents is very good. However, neuropsychiatric changes have been reported in association with montelukast, including dream abnormalities, insomnia, anxiety, depression, suicidal thinking, and in rare cases, suicide. Therefore, we do not prescribe montelukast to patients with active, pre-existing anxiety, depression, or symptoms that suggest psychiatric disorders. When initially prescribing this medication, we inform all patients about this potential side effect and advise them to stop the medication if they perceive adverse mood effects. (See «Antileukotriene agents in the management of asthma», section on ‘Adverse effects’.)

Ipratropium bromide — Ipratropium bromide, in the form of a 0.03 percent nasal spray, can be useful for decreasing rhinorrhea. It is a congener of atropine and may act by decreasing the release of substance P. However, it is less effective than glucocorticoid nasal sprays for sneezing, pruritus, or nasal obstruction [145]. Ipratropium bromide is also available in a stronger formulation (0.06 percent), although this is specifically labeled for reduction of rhinorrhea associated with colds.

Ipratropium is not recommended as a first-line drug in allergic rhinitis. It is sometimes useful in children or adults who have profuse rhinorrhea not otherwise controlled with topical nasal corticosteroids, a complaint most commonly observed in adult patients with concomitant allergic and nonallergic (or vasomotor) rhinitis. (See «Chronic nonallergic rhinitis», section on ‘Prominent rhinorrhea without other symptoms’.)

Therapies requiring caution — Nasal decongestant sprays and systemic glucocorticoids are therapies that can be highly effective if used infrequently and with caution and very problematic if used incorrectly.

Nasal decongestant sprays — Topical vasoconstrictor decongestants available include phenylephrine, oxymetazoline, xylometazoline, and naphazoline. Nasal decongestant sprays are NOT recommended as monotherapy in the chronic treatment of allergic rhinitis, as downregulation of the alpha-adrenergic receptor develops after three to seven days, and rebound nasal congestion may result. This can result in a cycle of nasal congestion both caused by and temporarily relieved by the medication, leading to escalating use and eventual dependency. This disorder is called rhinitis medicamentosa. (See «An overview of rhinitis», section on ‘Nasal decongestant sprays’.)

In contrast, the combination of a topical nasal decongestant and topical corticosteroid may effectively treat symptoms without causing rhinitis medicamentosa. (See ‘Combined with decongestant sprays’ above.)

Nasal decongestants are helpful when used just before air travel in patients who have difficulties with middle ear and/or sinus equilibration with flying or in patients who have problems with altitude changes. The long-acting agent, oxymetazoline, is administered twice per day and is approved for limited use in children older than six years and adults.

Systemic glucocorticoids — Short courses (ie, a few days) of oral glucocorticoids usually abolish symptoms of allergic rhinitis and may be indicated for severe allergic rhinitis symptoms that are preventing the patient from sleeping or working [6]. This approach was more widely used before nasal glucocorticoids and nonsedating antihistamines became available. However, systemic glucocorticoids should not be given repeatedly or for prolonged periods of time for the management of allergic rhinitis [146]. Similarly, we do not recommend injections of long-acting glucocorticoids for this condition, because of unpredictable absorption and the inability to dose adjust if side effects occur. (See «Major side effects of systemic glucocorticoids» and «Prevention and treatment of glucocorticoid-induced osteoporosis».)

ADJUNCTIVE AND OTHER THERAPIES

Nasal saline irrigation — Nasal irrigation with saline can be used alone for mild symptoms or just before other topical medications, so that the mucosa is freshly cleansed when the medications are applied (table 4).

A variety of over-the-counter devices, including squeeze bottles and bulb syringes are effective, provided the system delivers an adequate volume of solution (>200 mL per side) into the nose. Nasal irrigation with warmed saline can be performed as needed only, daily at baseline, or twice daily for increased symptoms.

Nasal irrigation is associated with improvement in a variety of rhinitis conditions and carries little risk if properly performed. Direct evidence for benefit in allergic rhinitis specifically includes the following studies [147-149]:

●One randomized study of the impact of nasal irrigation in children with acute sinusitis found that among those with concomitant allergic rhinitis, nasal irrigation significantly improved rhinorrhea, nasal congestion, throat itching, sleep quality symptoms, and nasal air flow [147]. A second study in children found that the effects of nasal irrigation were additive with those of intranasal glucocorticoids [149]. Nasal irrigation is particularly helpful when there are crusted nasal secretions due to chronic, thick drainage.

●Another randomized study of pregnant women found nasal saline irrigation to be beneficial for treatment of allergic rhinitis [148].

Patients can make their own irrigation solutions or buy commercially prepared solutions or kits. Patients should use distilled, sterilized, or previously boiled water because a small number of cases of primary amebic meningoencephalitis (PAM) have been contracted from using tap water that was contaminated with the amoeba Naegleria fowleri to perform sinus irrigation [150,151]. Although rare, PAM is usually fatal. N. fowleri is found worldwide and is usually contracted from swimming in freshwater lakes and rivers, geothermal heated bodies of water, or inadequately chlorinated pools [152]. Irrigation devices can also become contaminated with the bacteria present in the patient’s nasal cavities, although it is not clear that this causes any clinically significant problems. Still, irrigation devices should be cleaned as directed and replaced regularly [153].

Alternative and complementary therapies — Several alternative and complementary therapies are available for the treatment of allergic rhinitis and are reviewed separately. (See «Complementary and alternative therapies for allergic rhinitis and conjunctivitis».)

Patients with allergic rhinitis who are taking herbal therapies for other reasons should be aware of the following:

●St. John’s wort may decrease loratadine and fexofenadine levels, making these antihistamines less effective. (See ‘Adverse effects’ above.)

●Patients with weed pollen allergies should be cautious about taking Echinacea purpurea, which has extensive homology with ragweed pollen and has been implicated in anaphylaxis in atopic patients [154].

REFRACTORY SYMPTOMSSuspicion for chronic rhinosinusitis or rhinitis caused by other etiologies should be raised if a patient with presumed allergic rhinitis fails to improve significantly as a result of pharmacologic therapy and appropriate allergen avoidance. Evaluation for other conditions should be performed prior to pursuing allergen immunotherapy. (See «Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis» and «Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis», section on ‘Differential diagnosis’.)

REFERRALReferral to an allergist/immunologist should be considered for the following patients:

●Children with moderate-to-severe allergic rhinitis. Referral should be considered because allergen immunotherapy has been shown to alter the progression of allergic disease and subsequent development of asthma. (See «Subcutaneous immunotherapy for allergic disease: Indications and efficacy», section on ‘Preventive effects’.)

●Patients with prolonged or severe symptoms of rhinitis or significant residual symptoms despite pharmacologic therapy and avoidance measures.

●Patients whose management might be enhanced by identification of allergic triggers.

●Patients with coexisting asthma or nasal polyposis (referral to a pulmonologist or otolaryngologist, respectively, are other options for such patients).

●Patients with significant complications of allergic rhinitis, such as recurrent otitis media or recurrent sinusitis.

●Patients with intolerable adverse effects from medications or side effects that interfere with school/work productivity.

●Patients who are interested in immunotherapy as a treatment option.

●Patients who have required systemic glucocorticoids to control symptoms.

Patients who are able to discontinue antihistamines without experiencing intolerable symptoms should do so at least one week prior to their appointment, in case skin testing is indicated at the initial visit. Intranasal glucocorticoids and asthma medications do not interfere with skin testing and should NOT be discontinued. Patients with questions concerning which medications to continue or withhold should be instructed to contact the specialist’s office prior to their appointment. (See «Overview of skin testing for allergic disease».)

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See «Society guideline links: Rhinitis».)

INFORMATION FOR PATIENTSUpToDate offers two types of patient education materials, «The Basics» and «Beyond the Basics.» The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on «patient info» and the keyword(s) of interest.)

●Basics topics (see «Patient education: Seasonal allergies in adults (The Basics)» and «Patient education: Giving your child over-the-counter medicines (The Basics)» and «Patient education: Seasonal allergies in children (The Basics)»)

●Beyond the Basics topics (see «Patient education: Allergic rhinitis (Beyond the Basics)» and «Patient education: Trigger avoidance in allergic rhinitis (Beyond the Basics)»)

SUMMARY AND RECOMMENDATIONS

●In most patients, allergic rhinitis is a persistent condition that requires ongoing therapy over a period of years. Management combines allergen avoidance and pharmacologic therapy, with allergen immunotherapy added for refractory or severe cases. (See ‘Introduction’ above and «Subcutaneous immunotherapy for allergic disease: Indications and efficacy», section on ‘Indications’.)

●Glucocorticoid nasal sprays are the most effective single-agent maintenance therapy for allergic rhinitis and cause few side effects at the recommended doses. They are particularly effective in relieving nasal congestion. Specific agents include beclomethasone, flunisolide, budesonide, fluticasone propionate, mometasone furoate, fluticasone furoate, and ciclesonide (table 3). Mometasone furoate, fluticasone furoate, and triamcinolone acetonide are approved by the US Food and Drug Administration (FDA) for use in children ≥2 years. Dry powder formulations are also available in the United States and some other countries. (See ‘Glucocorticoid nasal sprays’ above.)

●First-generation sedating antihistamines are familiar to patients and available without a prescription, but they have several significant adverse effects, including sedation and impairment of cognitive function, paradoxical agitation in young children, and anticholinergic side effects in older adults. Second-generation agents, such as cetirizine, levocetirizine, loratadine, desloratadine, and fexofenadine have few of these problems and are preferred when antihistamine therapy is desired. (See ‘Oral antihistamines’ above.)

●For patients with mild or intermittent symptoms, we suggest a glucocorticoid nasal spray (Grade 2A). We start at the maximal recommended dose for age and then taper to the lowest effective dose once symptoms are controlled. (See ‘Glucocorticoid nasal sprays’ above.)

●Some patients with mild symptoms may prefer other agents because of oral administration or desire to avoid glucocorticoids. Thus, the following are appropriate choices as well:

•An antihistamine nasal spray, such as azelastine or olopatadine, administered regularly or as needed. (See ‘Antihistamine nasal sprays’ above.)

•A second-generation oral antihistamine, administered regularly or as needed. (See ‘Second- and third-generation antihistamines’ above.)

•Cromolyn nasal spray, administered regularly or as needed. This is often preferred by parents of young children because of its excellent safety profile, although it is less effective than other agents. (See ‘Cromolyn sodium’ above.)

●For patients with persistent or moderate-to-severe symptoms, we recommend glucocorticoid nasal sprays as first-line therapy (table 3) (Grade 1A). Several agents, such as fluticasone propionate, mometasone furoate, and fluticasone furoate, have minimal systemic bioavailability and are conveniently dosed once or twice daily. We start at the maximal recommended dose for age and then taper to the lowest effective dose once symptoms are controlled. (See ‘Glucocorticoid nasal sprays’ above and ‘Persistent or moderate-to-severe symptoms’ above.)

●If glucocorticoid nasal sprays alone are not sufficient to control symptoms, we suggest adding an antihistamine nasal spray (such as azelastine or olopatadine) in preference to other agents (Grade 2B). A nasal spray containing both azelastine and fluticasone is available in the United States. Other options include an oral antihistamine/decongestant combination or montelukast. (See ‘Combination corticosteroid/antihistamine sprays’ above and ‘Persistent or moderate-to-severe symptoms’ above.)

●For patients with rhinitis symptoms that are refractory to glucocorticoid nasal sprays and concomitant asthma or nasal polyposis, the addition of montelukastmay be helpful. (See ‘Montelukast’ above and ‘With concomitant asthma’ above.)

●For patients with rhinitis refractory to a glucocorticoid nasal spray and concomitant allergic conjunctivitis, we suggest the addition of an antihistamine eye drop, rather than the addition of an oral antihistamine (Grade 2B). However, patients with severe symptoms may require all three agents to attain adequate relief. (See ‘With concomitant allergic conjunctivitis’ above.)

●Chronic rhinosinusitis or mixed rhinitis should be suspected if a patient with presumed allergic rhinitis fails to improve significantly as a result of pharmacologic therapy and appropriate allergen avoidance. (See ‘Refractory symptoms’ above.)

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