The Medical Letter on Drugs and Therapeutics
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Drugs for Allergic Disorders
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ALLERGIC RHINITIS
 

Allergic rhinitis can be classified as seasonal, perennial, or episodic. It is often associated with allergic conjunctivitis, rhinosinusitis, and asthma.1,2

H1-ANTIHISTAMINES — Oral – Oral second-generation H1-antihistamines are the preferred first-line treatment for relief of the itching, sneezing, and rhinorrhea that characterize mild-to-moderate allergic rhinitis. They are less effective for nasal congestion.

Adverse Effects – Second-generation H1-antihistamines penetrate poorly into the central nervous system (CNS) and are significantly less likely than first-generation agents to impair CNS function and cause sedation.3,4 Fexofenadine is nonsedating and free of CNS-impairing effects, even in higher-than-recommended doses. Loratadine and desloratadine are nonimpairing and nonsedating in recommended doses, but may cause sedation at higher doses. Cetirizine and levocetirizine can cause sedation in recommended doses.

First-generation H1-antihistamines such as diphenhydramine (Benadryl, and generics) can cause CNS impairment with or without sedation. They can interfere with learning and memory, impair performance on school examinations, decrease work productivity, and increase the risk of on-the-job injuries, car accidents, and even plane crashes.5 When these medications are taken at night, adverse effects on wakefulness and psychomotor performance can persist the next day.6 Cumulative exposure to drugs with anticholinergic effects such as first-generation antihistamines has been associated with dementia.7

Intranasal – Intranasal H1-antihistamines have a rapid onset of action. Their clinical efficacy in allergic rhinitis, including relief of nasal congestion, is equal or superior to that of oral H1-antihistamines. An intranasal combination of the H1-antihistamine azelastine and the corticosteroid fluticasone propionate has improved symptoms more than either drug alone in patients with seasonal allergic rhinitis.8 Intranasal antihistamines can cause nasal discomfort, epistaxis and headache, and may cause somnolence.

INTRANASAL CORTICOSTEROIDS — Intranasal corticosteroids are the most effective drugs available for prevention and relief of allergic rhinitis symptoms, including itching, sneezing, discharge, and congestion. They are the drugs of choice for moderate-to-severe disease. Most of these agents are effective when given once daily. The onset of action typically occurs within 12 hours, but maximal effects may not be achieved for ≥7 days. In patients with seasonal allergic rhinitis, intranasal corticosteroid sprays can decrease ocular as well as nasal symptoms.9 Several intranasal corticosteroids are now available without a prescription (see Table 2).10

Adverse Effects – Intranasal corticosteroids can cause mild dryness, irritation, burning and bleeding of the nasal mucosa, sore throat, epistaxis, and headache. Ulceration, mucosal atrophy, and septal perforation can occur; patients should be examined periodically to detect changes in the nasal mucosa. Increased intraocular pressure has been reported. Use of intranasal corticosteroids for ≥12 months in children has been associated with small decreases in growth velocity.

MONTELUKAST — Release of cysteinyl leukotrienes in the nasal mucosa during allergic inflammation leads to nasal congestion. The leukotriene receptor antagonist montelukast is FDA-approved for treatment of seasonal and perennial allergic rhinitis. It provides modest relief of sneezing, itching, discharge, and congestion, but it is less effective than an intranasal corticosteroid.11 Montelukast is generally considered safe.

DECONGESTANTS — Oral – Oral decongestants such as phenylephrine and pseudoephedrine act as vasoconstrictors in the nasal mucosa, primarily through stimulation of alpha-1 adrenergic receptors on venous sinusoids. They only relieve congestion, not sneezing, itching, or discharge. They are often used in combination with an H1-antihistamine. Tolerance to the decongestant effect can occur.

Phenylephrine has replaced pseudoephedrine in many oral decongestant products because illicit pseudoephedrine use has resulted in sales restrictions. In an open-label, randomized, dose-ranging study, phenylephrine was no more effective than placebo for relief of nasal congestion in 539 patients with seasonal allergic rhinitis who took up to 4 times the typical dose of 10 mg.12

Potential adverse effects of oral decongestants include insomnia, excitability, headache, nervousness, anorexia, palpitations, tachycardia, arrhythmias, hypertension, nausea, vomiting, and urinary retention. These drugs should be used cautiously in patients with cardiovascular disease, hypertension, diabetes, hyperthyroidism, closed-angle glaucoma, or bladder neck obstruction.

Intranasal – Intranasal decongestants such as oxymetazoline (Afrin, and generics) are less likely than oral decongestants to cause systemic adverse effects, but they can cause stinging, burning, sneezing, and dryness of the nose and throat. In order to avoid rhinitis medicamentosa (rebound congestion), they should not be used for more than 3-5 consecutive days. Rhinitis medicamentosa associated with prolonged use is treated by discontinuing the intranasal decongestant and using an intranasal corticosteroid instead. In a cross-sectional, observational study, nasal congestion was the predominant symptom in 895 patients who self-medicated for moderate-to-severe persistent rhinitis. The prevalence of intranasal decongestant overuse was high, and was inversely related to intranasal corticosteroid use.13

CROMOLYN — Use of intranasal cromolyn sodium before allergen exposure inhibits mast cell degranulation and mediator release, preventing allergic rhinitis symptoms. It is relatively free from adverse effects, but must be used 3-4 times daily and is considerably less effective than an intranasal corticosteroid.14

IPRATROPIUM — Ipratropium bromide, a quaternary amine antimuscarinic agent, is poorly absorbed systemically and does not readily cross the blood-brain barrier. Intranasal ipratropium can be useful in patients whose primary symptom is nasal discharge. It does not relieve sneezing, itching, or congestion.

Adverse Effects – Ipratropium can cause dry nose and mouth, epistaxis, and pharyngeal irritation. After inadvertent instillation in the eye, it can increase intraocular pressure and should be used with caution in patients with glaucoma.

OMALIZUMAB — Omalizumab (Xolair), a monoclonal antibody approved by the FDA for treatment of allergic asthma and chronic urticaria, has a dose-dependent beneficial effect in seasonal allergic rhinitis. Injected subcutaneously every 2-4 weeks, it decreases free IgE levels in serum and the number of IgE receptors on mast cells and basophils. In a systematic review and meta-analysis of 11 studies that included 2870 patients with inadequately controlled allergic rhinitis, injection of omalizumab significantly reduced daily nasal symptom severity scores and rescue medication use and improved quality of life. Adverse effects did not differ from placebo.15 Omalizumab is generally well tolerated, but it has caused anaphylaxis in about 0.1% of patients with asthma.

ORAL CORTICOSTEROIDS — A short course of an oral corticosteroid can be effective in patients with severe allergic rhinitis or rhinitis medicamentosa who cannot tolerate or do not respond to other drugs.

ALLERGEN-SPECIFIC IMMUNOTHERAPY — Immunotherapy can alter the natural history of allergic respiratory disease.

PREGNANCY — In a systematic review and meta-analysis of 37 studies that included >50,000 women exposed to H1-antihistamines during the first trimester of pregnancy, use of these drugs was not associated with an increased risk of major malformations, spontaneous abortions, prematurity, or low birth weight.16 Nasal saline irrigations, cromolyn sodium, and intranasal corticosteroids are also considered safe for pregnant women with allergic rhinitis.17

 
ALLERGIC CONJUNCTIVITIS
 

Allergic conjunctivitis, although underreported, probably occurs in the majority of patients with allergic rhinitis. Symptoms such as itching, redness, tearing, and photophobia are frequently seasonal. Nonpharmacologic management includes allergen identification and avoidance, use of cool compresses, and avoidance of eye rubbing and contact lens wearing during symptomatic periods. Optimal management of allergic rhinitis with an oral second-generation H1-antihistamine and an intranasal corticosteroid can benefit concomitant allergic conjunctivitis as well.18

OPHTHALMIC DRUGS — Ophthalmic antihistamines are at least as effective as oral H1-antihistamines for treatment of allergic conjunctivitis. Onset of action occurs within a few minutes. Starting treatment before the pollen season may be more beneficial in controlling symptoms than waiting for them to occur. Alcaftadine,19 azelastine, bepotastine, epinastine, and olopatadine are marketed as having both H1-antihistamine and mast-cell-stabilizing activity, as is ketotifen, which is available over the counter. A meta-analysis of four studies in a total of 204 patients has suggested that olopatadine may be more effective than ketotifen in improving some ocular symptoms.20

The ophthalmic mast cell stabilizers cromolyn, lodoxamide, and nedocromil have a slower onset of action than ophthalmic H1-antihistamines and are mostly used for treatment of mild-to-moderate symptoms.

The topical nonsteroidal anti-inflammatory drug ketorolac is less effective than ophthalmic H1-antihistamines.

Ophthalmic decongestants such as naphazoline reduce erythema, congestion, itching, and eyelid edema, but they have a short duration of action and can cause burning, stinging, rebound hyperemia, and conjunctivitis medicamentosa. Ophthalmic antihistamine/decongestant combinations available over the counter such as pheniramine/naphazoline (Visine A, and generics) and antazoline/naphazoline (Vasocon-A) have similar adverse effects.

Ophthalmic corticosteroids can be considered for use in allergic conjunctivitis that fails to respond to other medications. Loteprednol is inactivated rapidly in the anterior chamber of the eye and has been associated with significantly lower rates of intraocular pressure elevation than ophthalmic administration of prednisolone or dexamethasone.21 Treatment with ophthalmic corticosteroids should be limited to two weeks, and even during this brief exposure, patients should be monitored for exacerbations of conjunctival or corneal viral infections and for increased intraocular pressure. With longer treatment, cataract formation is a concern.

STINGING AND BURNING — Patients who find that application of any topical ophthalmic preparation leads to stinging or burning should try refrigerating the drug before use. Compounding pharmacies can prepare preservative-free formulations for patients with ocular hypersensitivity to preservatives in ophthalmic drugs. A novel filter device has been developed for removal of benzalkonium chloride, the most common offender.22

 

 
ATOPIC DERMATITIS
 

Atopic dermatitis (also known as atopic eczema) commonly presents in infancy and early childhood and is frequently associated with allergic rhinitis and asthma. Skin hydration followed by application of moisturizers and emollients is highly recommended and can reduce disease severity when combined with topical drugs.23 Avoidance of irritating soaps, detergents or clothing, extremes of temperature and humidity, and keeping fingernails trimmed are all helpful in the management of atopic dermatitis symptoms. In some patients with atopic dermatitis exacerbated by food or other allergens, confirmation of the trigger and elimination of the relevant allergen may be helpful.

TOPICAL DRUGS — Corticosteroids – A medium- or high-potency topical corticosteroid may be needed to achieve control of skin inflammation in atopic dermatitis. For maintenance treatment, the lowest potency topical corticosteroid that is effective in a given patient should be used. High-potency corticosteroids such as betamethasone dipropionate 0.05% ointment or cream should only be applied to the trunk and extremities for short periods of time and should never be applied to the face or intertriginous areas such as the axillae and groin. Low-potency corticosteroids such as hydrocortisone cream are safe for use on the face and intertriginous areas.

Use of topical corticosteroids can lead to development of striae and skin atrophy. When applied to the eyelids for prolonged periods, they can potentially cause glaucoma and cataracts. The risks of systemic adverse effects, including adrenal suppression and possibly lymphoma, increase with corticosteroid potency, percentage of body surface covered, and duration of treatment. The risks are greatest when high-potency corticosteroids are applied under occlusive dressings in infants and young children with widespread skin involvement who require long-term treatment.

Calcineurin Inhibitors – Topically applied tacrolimus and pimecrolimus can reduce inflammation and itching associated with atopic dermatitis within a few days. Topical tacrolimus 0.1% is similar in efficacy to a medium-potency topical corticosteroid and may be considered for use in patients with topical corticosteroid-resistant atopic dermatitis, especially on the face or intertriginous areas where corticosteroid adverse effects can be troublesome. It can also be used as maintenance treatment to minimize use of topical corticosteroids. After control of inflammation is achieved, applying tacrolimus ointment 2-3 times weekly increases the number of flare-free days and the time to relapse. Pimecrolimus is not as effective as a medium-potency topical corticosteroid, but it can be useful as steroid-sparing therapy for mild-to-moderate atopic dermatitis.

Tacrolimus and, less often, pimecrolimus can cause mild, transient itching, burning, stinging, and erythema, and both have been associated with an increased risk of viral skin infections such as herpes simplex and varicella zoster, but they do not cause cutaneous atrophy. Rare postmarketing reports of malignancies in patients treated with topical calcineurin inhibitors led the FDA to include a boxed warning in the labels of these drugs about possible risks of lymphoma and other cancers with prolonged treatment. A causal relationship has not been established.24

Crisaborole – Crisaborole (Eucrisa), a topical phosphodiesterase type-4 (PDE4) inhibitor, has been approved by the FDA for treatment of atopic dermatitis in patients ≥2 years old. It acts in part by increasing levels of cyclic adenosine monophosphate (cAMP) to suppress production of proinflammatory cytokines in the skin. Systemic absorption is minimal.25 In two randomized controlled trials in patients with mild-to-moderate atopic dermatitis, crisaborole 2% ointment applied twice daily to affected areas of skin was compared to its vehicle alone. A significantly higher percentage of patients using crisaborole achieved clear or almost-clear skin in both trials (33% vs 25% and 31% vs 18%).26 Adverse effects have been mainly stinging and burning at the application site. The drug's long-term adverse effects are unknown. How crisaborole compares to topical corticosteroids or calcineurin inhibitors remains to be established.

Coal Tar – Coal tar preparations have antipruritic and anti-inflammatory effects, but they are messy and odoriferous and are now seldom used except in shampoo formulations. Adverse effects include skin irritation, folliculitis, and photosensitivity.

Antipruritic Therapy – Pruritus is optimally controlled by regular applications of topical anti-inflammatory medications to the skin. Although the efficacy of oral H1-antihistamines in atopic dermatitis has not been confirmed in randomized controlled trials, some physicians recommend a first-generation sedating H1-antihistamine such as diphenhydramine or hydroxyzine (Vistaril, and generics) at bedtime. Topical H1-antihistamines are potentially sensitizing and are therefore contraindicated for use in atopic dermatitis.27

SYSTEMIC DRUGS — Dupilumab (Dupixent), a subcutaneously-injected, fully human monoclonal antibody that inhibits the signaling of the inflammatory cytokines interleukin (IL)-4 and IL-13, has been approved by the FDA for treatment of adults with moderate-to-severe atopic dermatitis that has not responded to topical therapies.28 In two randomized, double-blind, 16-week trials in 1379 adults, dupilumab monotherapy significantly improved measures of skin clearing, overall extent and severity of disease, and pruritus compared to placebo. A score of clear or almost clear on the Investigator's Global Assessment scale and a reduction of ≥2 points on that score from baseline, the primary endpoint, occurred in 38% and 36% of patients treated with dupilumab every other week in the two trials versus 10% and 8% of those who received placebo.29 Administration of dupilumab in combination with topical corticosteroids for 52 weeks significantly improved skin clearing and overall disease severity compared to use of topical corticosteroids alone.30 Adverse effects have included injection-site reactions, conjunctivitis, blepharitis, keratitis, and oral herpes and other herpes simplex virus infections.

Cyclosporine (Neoral, and generics) is not FDA-approved for use in atopic dermatitis, but it has been recommended for short-term treatment of moderate-to-severe atopic dermatitis that is refractory to topical therapy.31 In multiple randomized controlled trials, it significantly decreased disease activity within 2 to 6 weeks.32 The usual dosage is 3-6 mg/kg/day (150-300 mg/day in adults). Cyclosporine can cause hypertension, nephrotoxicity, GI disturbances, hirsutism, headache, paresthesias, hypertriglyceridemia, and musculoskeletal or joint pain. It also increases the risks of infection and cutaneous and lymphoproliferative malignancies, and it interacts with many other drugs.

Short courses of an oral corticosteroid such as prednisone can be helpful in severe acute exacerbations of atopic dermatitis, but the drug should be tapered quickly and intensified treatment with topical corticosteroids and calcineurin inhibitors should be started.

PHOTOTHERAPY — Phototherapy in moderation has been effective in some patients after failure of topical drugs. It can be used alone or in combination with emollients and topical corticosteroids.31

 

 
URTICARIA
 

Acute urticaria is a self-limited condition that responds well to treatment with an oral H1-antihistamine. Chronic urticaria (≥6 weeks) can last for months, years, or decades.

H1-ANTIHISTAMINES — Randomized controlled trials have shown that oral second-generation H1-antihistamines consistently decrease itching and reduce the number, size, and duration of wheals in acute and chronic urticaria.33 Taken regularly, they can prevent new wheals from appearing. Cetirizine and levocetirizine are more potent in suppressing histamine-induced wheals than fexofenadine, and fexofenadine is more potent than loratadine and desloratadine. High doses (up to 4 times the usual dose) of a second-generation H1-antihistamine are recommended (off-label) for treatment of chronic urticaria that does not respond to standard doses.34 Despite decades of use in urticaria, first-generation H1-antihistamines have never been optimally studied in randomized controlled trials, and they can cause CNS impairment with or without sedation. Nevertheless, when even higher-than-usual doses of an oral second-generation H1-antihistamine fail to adequately control symptoms, some clinicians have found that hydroxyzine or diphenhydramine can be helpful.

OMALIZUMAB — Omalizumab is FDA-approved for treatment of chronic idiopathic urticaria refractory to H1-antihistamines.35 In randomized placebo-controlled trials, subcutaneous injections of omalizumab every 4 weeks significantly reduced itch and wheal scores and significantly increased rates of complete response; the highest response rates occurred with a 300-mg dose.36 Omalizumab also significantly reduced the angioedema that was associated with urticaria in some patients.37,38 Adverse events were similar to those with placebo. No patients developed anaphylaxis, which has occurred with use of omalizumab in patients with asthma.

OTHER DRUGS — A short course (3-7 days) of an oral corticosteroid such as prednisone 1 mg/kg (maximum dose 50 mg) can be helpful in relieving severe exacerbations of itching and whealing in chronic urticaria. Topical corticosteroids are not effective.

Cyclosporine is recommended in guidelines as a low-cost alternative to omalizumab in H1-antihistamine-refractory chronic urticaria. Although not FDA-approved for this indication, it has been effective in randomized controlled trials.39 Patients taking cyclosporine require monitoring of blood pressure and renal function. In one small randomized controlled trial, use of dapsone 100 mg/day to treat antihistamine-refractory chronic urticaria led to a significant improvement in symptoms40; monitoring of complete blood counts and hepatic function is required, and dapsone should not be used in G6PD-deficient patients.

In some randomized controlled trials, the leukotriene receptor antagonist montelukast had a beneficial effect in H1-antihistamine-refractory chronic urticaria, but results have been inconsistent. Montelukast is not FDA-approved for treatment of urticaria, but it has been recommended in some guidelines as an alternative when other treatments have failed.41

Other immunomodulators such as systemic tacrolimus, mycophenolate mofetil, and hydroxychloroquine have been recommended for treatment of urticaria based on anecdotal experience.41,42

 
ALLERGEN-SPECIFIC IMMUNOTHERAPY
 

Sublingual immunotherapy (SLIT) has been approved by the FDA for treatment of allergic rhinitis induced by grass pollen, ragweed pollen, and dust mites.43 Both subcutaneous immunotherapy (SCIT) and SLIT are effective in altering the natural history of allergic respiratory disease and inducing long-term remission, but SCIT has been used much longer, and has been highly effective in preventing future anaphylactic reactions to insect stings. Both SCIT and SLIT may be beneficial in decreasing symptoms and rescue medication use in patients with allergic rhinitis. Definitive randomized controlled trials comparing SCIT with SLIT are needed.44

Local adverse effects of SCIT include pain and swelling at injection sites. Anaphylaxis and, very rarely, death can occur. SCIT should only be administered under medical supervision. After dose buildup, maintenance injections are typically continued at monthly intervals for 4-5 years.

SLIT can cause local adverse effects such as mouth and ear pruritus, mouth edema, and throat irritation. Systemic adverse effects include nausea and mild abdominal pain. Anaphylaxis is rare and fatalities have not been reported.45 Maintenance treatment is self-administered at home.

Advances have been made in immunotherapy for prevention of allergic reactions to peanuts and other foods. Oral, sublingual, and epicutaneous routes of administration are being investigated.46 No immunotherapy is currently approved by the FDA for treatment of food allergy.

 
ANAPHYLAXIS
 

Anaphylaxis, a multi-system allergic reaction that is rapid in onset and may cause death, often occurs in community settings where it is typically triggered by a food, insect sting, or medication. The incidence of anaphylaxis is increasing in the US population. The greatest increase has been reported in food-related anaphylaxis, which occurs most commonly in the pediatric population.47 Vaccine-triggered anaphylaxis remains rare.48 Patients at risk for anaphylaxis in community settings should receive printed information about how to avoid their relevant triggers.49 Those who have had an anaphylactic reaction triggered by stinging insects should be instructed in insect avoidance measures and referred to an allergy/immunology specialist for immunotherapy with standardized extracts of insect venom or whole-body extract from fire ants.50

EPINEPHRINE — All patients at risk for anaphylaxis recurrence in community settings and caregivers of children at risk should be equipped with one or more epinephrine auto-injectors such as EpiPen or Auvi-Q (or generic epinephrine for injection) and trained to recognize anaphylaxis and use the auto-injector correctly and safely. There are no absolute contraindications to epinephrine injection in anaphylaxis. Concerns about potential adverse effects in the elderly and in patients with cardiovascular disease need to be weighed against the possibility of death from anaphylaxis.51

Injection of epinephrine 0.3 mg from either Auvi-Q or EpiPen results in similar peak epinephrine levels and total epinephrine exposure.52 Auvi-Q, reintroduced in the US in 2017, has a compact rectangular shape and provides visual signals and step-by-step audio instructions for use. Compared with pen-type auto-injectors, it is more convenient to carry and easier to use, has additional safety features including an automatic fully retractable needle, and is less likely to cause unintentional injuries.53,54

The recommended dose of epinephrine is 0.01 mg/kg (0.5 mg maximum) intramuscularly. However, all epinephrine auto-injectors provide epinephrine in fixed doses of 0.15 or 0.3 mg. Auto-injectors containing 0.15 mg are labeled for children weighing 15-30 kg, and those containing 0.3 mg are labeled for adults and children weighing ≥30 kg. No auto-injector provides an optimal dose for children weighing between 15 and 30 kg; some clinicians prescribe an auto-injector containing 0.3 mg for children who weigh ≥25 kg. Since no weight-appropriate low dose for infants is available in any auto-injector, many physicians prescribe a 0.15-mg auto-injector (off-label) for this age group.55

After injection of epinephrine, patients should be taken to the nearest emergency department for observation because anaphylaxis symptoms recur within hours in up to 20% of patients. Intravenous fluids and oxygen may be required in cases of severe anaphylaxis. H1-antihistamines and corticosteroids are not recommended for treatment of anaphylaxis in community settings; they do not prevent or relieve airway obstruction, hypotension or shock, or prevent death.

 
INSECT STINGS AND BITES
 

Small local allergic reactions to insect stings and bites (itchy red swellings) are self-limited. Large local reactions that occur at the sites of stings from honeybees, yellowjackets, wasps, and fire ants, or bites from mosquitoes, deer flies, and other insects, can involve a large portion of the face or an entire extremity and cause extreme discomfort. For prevention and treatment of large local reactions, an oral second-generation H1-antihistamine such as cetirizine should be used as soon as possible after the sting or bite. For mild or moderate large local reactions, a topical corticosteroid cream can be applied to the affected area for 5-7 days. Oral prednisone 1 mg/kg once daily (maximum daily dose 50 mg) for 5-7 days may be needed for severe large local reactions. Although the risk of anaphylaxis in patients with large local reactions to stinging insects is <5%, epinephrine auto-injectors are often prescribed for these patients. Venom immunotherapy is effective in preventing large local reactions and can be considered for those with occupational or other unavoidable exposure to stinging insects who frequently require treatment for reactions to stings.56

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