From The Institute for Community Pharmacy A Nonprofit Publication Volume 1 (Issue 4) September 2003 Clinical Practice Review Drugs for Allergy Introduction Allergic rhinitis is the sixth most common chronic illness. Recent estimates have determined that 10% to 30% of adults and up to 40% of children have allergic rhinitis (US Dept of Health and Human Services. AHRQ, Pub No 02-E023, May 2002). This may not be an accurate estimation because many patients do not go to their doctor for treatment but rely on over-the-counter treatment and advice of their pharmacists to manage their symptoms. Over the past 30 years there has been a significant increase in the prevalence of allergic rhinitis in developed countries. Theories for this increased prevalence abound, including the hygiene hypothesis (Strachan DP:BMJ 1989;299:1259-60), environmental factors, and others. The good news is that current therapeutic options do improve the quality of life and allow patients to control their symptoms and reduce the impact of allergic rhinitis on their lifestyles. Impact of Allergic Rhinitis Allergic rhinitis is characterized by symptoms of sneezing, runny nose, congestion, and nasal itching. Other symptoms include red, watery, itchy eyes and impaired sense of smell. Allergic rhinitis can significantly reduce energy, negatively affect behavior in children, and impair learning. Allergic rhinitis can lead to reduced worker productivity and increased school absenteeism (Juniper EF: Allergy 1997;52:971-977). The cost of allergic rhinitis is larger than just the direct cost of care. It is estimated that approximately $2 billion per year is spent on direct cost of care for allergic rhinitis. The indirect cost is far greater and much harder to estimate. One study estimated the annual indirect cost at $3.8 billion, which includes lost work productivity (US Dept of Health and Human Services. AHRQ, Pub No 02-E023, May 2002). For children, there are approximately 2 million lost school days per year due to allergic rhinitis (Dykewicz MS: Ann Allergy Asthma Immunol 1998:81(5 PT 2):478-518. The Importance of Allergic Rhinitis Co-morbidities When consulting with patients with allergic rhinitis, the pharmacist must be aware of several co-morbidities that are often associated with allergic rhinitis. This is important because failure to address medication issues with a holistic approach may fail to identify potential worsening of these co-morbidities. Asthma There is a definite connection between asthma and allergic rhinitis and the majority of patients with asthma also have seasonal and perennial allergic rhinitis (Bosquet J:J Allergy Clin Immunol 2001:108(suppl 5):S147-S334). Rhinitis has been shown to coexist in over 75% of patients with allergic asthma and in over 80% of patients with non-allergic asthma (Sibbald B:Thorax 1991:46:895-901). Pharmacists are referred to a 1999 World Health Organization expert panel that reclassified allergic rhinitis. The panel developed a document called “Allergic Rhinitis and Its Impact on Asthma” (ARIA). This panel has changed the terms used to classify allergic rhinitis. Instead of using the terms “seasonal” and “perennial” to classify allergic rhinitis, they were changed to “intermittent” and “persistent” which more closely reflect the duration of the disease, and to “mild”, “moderate”, and “severe”, which indicate the severity of symptoms (Bosquet J:J Allergy Clin Immunol 2001:108(suppl 5):S147-S334). The ARIA guidelines clarify the relationship between asthma and rhinitis as common co-morbidities. They suggest the concept that asthma and rhinitis are the same disease in one continuous airway. The ARIA guidelines are important to the pharmacist because they point out that the patient with persistent allergic rhinitis should be evaluated for asthma and that patients with asthma should be evaluated for allergic rhinitis. The question remains. Does allergic rhinitis precede asthma? Some studies do suggest such a relationship: however much more research is needed to identify the pathogenesis (Samolinski B: Otolaryngol Pol 2002:56:49-55). We know that allergic rhinitis is a common trigger for asthma (Simon RA: Allergy Asthma Proc 2002;23:219-222). Attention must be focused on the diagnosis of allergic rhinitis because it can confound the diagnosis of asthma and exacerbate existing asthma. The ARIA guidelines encourage the early diagnosis and treatment of allergic rhinitis to avoid subsequent asthma development. It is important that the most effective and safe pharmaceutical treatment be aimed at both upper and lower airway disease. Other Co-morbid Conditions In addition to asthma, allergic rhinitis is associated with other co-morbid conditions including sinusitis, conjunctivitis, otitis media, pharyngitis, laryngitis, snoring, and sleep apnea. Many of the pathophysiologic mechanisms are poorly understood. These co-morbid conditions increase morbidity and costs; therefore it is important that timely and effective treatment of allergic rhinitis be implemented to help prevent the onset or worsening of any co-morbid conditions. Pathophysiology of Allergic Rhinitis Many different inflammatory cells are involved in the complex allergic inflammatory response. These cells release chemical mediators that interact with end-organ receptors resulting in various clinical manifestations of allergic rhinitis. The allergic reactions involve both early- and late-phase responses. The early-phase response results from IgE antibodies binding to tissue mast cells. IgE antibodies interact when exposed to an allergen and cause the release and formation of chemical mediators. The chemical mediators primarily involved in the early-phase response are histamine, leukotrienes, bradykinin, and other chemical mediators. Late-phase reactions occur several hours after the early-phase reaction and are due to infiltration of eosinophils, basophils, monocytes, and lymphocytes in the area of the early-phase reaction. The late-phase response results in priming and airway hyperresponsiveness. Priming occurs where there is upregulation in the area of inflammation and upon secondary exposure to allergen, results in a more intense response to the allergen. Latephase response not only involves cells but chemical mediators including histamine and leukotrienes. More and more the epithelium of the nasal mucosa is being recognized as a highly active tissue with cell populations providing cytokines and other chemical mediators important in localized tissue cell recruitment. Accumulation of mast cells, basophils, eosinophils, and T cells in the inflamed tissue is responsible for the release of cytokines such as interleukin-4 and interleukin-5 within the nasal mucosa. Once induced these cells and related chemical mediators can cause persistent inflammation for several weeks after allergen exposure. In patients with perennial allergic rhinitis, continuous low-dose exposure results in persistent nasal inflammation. Therapeutic Options Environmental Allergen avoidance is usually the first measure taken to reduce the symptoms of allergic rhinitis. Many allergens can be avoided, such as house dust mites, pets, mold, and occupational agents. Total avoidance, however may not be possible or practical. Simple changes can be made in the home to reduce allergen exposure. Pet avoidance is often the most effective but not followed. At a minimum, pets should be removed from the bedroom. Other avoidance efforts include highefficiency particulate air (HEPA) filtration and control of dust mites, molds, and pollen exposure. Table 1: Allergen avoidance techniques Allergen Avoidance measures Dust mites Dust mite covers on pillows, mattresses, and box springs Wash bedding at least 2x per week in hot water Keep humidity below 50% Remove carpeting and replace with wood, tile, or linoleum floors Use blinds instead of curtains for window coverings Remove stuffed animals or wash or freeze 1-2x per week Mold Remove carpets from the bedroom Remove live plants to avoid mold in the soil Run air conditioning and change filters frequently Keep windows closed Pollen Avoid outdoor activities during high pollen counts Usually low yield but worth an effort Pharmacotherapy The development of the ARIA guidelines has had a dramatic impact on the selection of pharmacotherapy for treatment of allergic rhinitis. It is no longer appropriate to stick with the old scenario of step therapy where patients were initiated on OTC antihistamines followed by intranasal corticosteroids and/or oral prescription antihistamines. Current treatment options and approaches are far more targeted at the individual patient symptom pattern and severity. There are several general pharmacologic approaches to treatment of allergic rhinitis (Nash D et al: Am J Managed Care 2000(6) suppl: S3S15 ) . These include: The goal of pharmacologic therapy is to alleviate and prevent patient symptoms. Individualize therapy based on symptoms and severity. Antihistamines are effective for rhinorrhea, pruritus, and sneezing but are not generally effective for treating nasal blockage or congestion. Care should be used and patients instructed on the potential inhibition of mental acuity when using the sedating antihistamines. Caution patients regarding sedating antihistamines and document in the record. Intranasal steroids are first line therapy when congestion and blockage are major symptoms. In clinical trials intranasal corticosteroids are generally considered more effective than antihistamines. Patients must be instructed to use their nasal steroid inhalers regularly to get the maximum benefit. Combination therapy of a nasal steroid and antihistamine do not produce better results than single agent therapy when symptoms are not severe. Table 2 offers an overall approach to pharmacologic management of allergic rhinitis and is based on symptoms and severity. Table 2: Symptomatic Approach to Allergic Rhinitis Pharmacotherapy Considerations Intermittent Symptoms Educate on Triggers Persistent Mild to Moderate Symptoms Mild - No interference with sleep or ADL's Moderate - Interference with sleep and ADL's Intranasal corticosteroids (INCS) Work best if started 1 – 2 weeks before the allergy season and continued daily through the season Is the most effective class of medication for controlling symptoms of allergic rhinitis. Effective for reducing nasal congestion and partially relieving ocular itching Adults INCS Or Oral non-sedating antihistamine (NSA) with or without decongestant (depending on presence or absence of congestion/blockage) Clarinex 5mg QD Allegra 60 mg BID or 180mg QD (not approved for perennial allergic rhinitis) Or Topical nasal antihistamine Astelin Or Leukotriene antagonist Singulair Children INCS Nasonex in children 3 years or older or Flonase age 4 years and older Claritin (RediTab®) 10mg QD dose for ages 6 years and above. Claritin Syrup QD dosed as a single 5mg dose for ages 2 years Eye symptoms: Topical Ocular Products Antihistamine Mast cell stabilizer Topical NSAID Severe Symptoms Consider referral to Allergy Severe - Interference with sleep, ADL's , and long duration Intranasal corticosteroids (INCS)l Adults INCS And Oral non-sedating antihistamine (NSA) - with or without decongestant (depending on presence or absence of congestion) Clarinex 5mg QD Allegra 60 mg BID or 180mg QD (not approved for perennial allergic rhinitis) And/Or Topical nasal antihistamine Astelin And if needed Short course of oral corticosteroids – 3 to10 days – especially in presence of severe blockage Children INCS Nasonex in children 3 years and older or Flonase age 4 years and older Claritin (RediTab®) 10mg QD dose for ages 6 years and above. Claritin Syrup QD dosed as a single 5mg dose for ages 2 years Nasal Cromolyn (Nasalcrom) Eye symptoms Topical Ocular Products Antihistamine Mast cell stabilizer Topical NSAID Intranasal saline wash OTC oral antihistamines Loratadine 10mg tablets (OTC) Claritin (RediTab®) 10mg dose for ages 6 years and above. Claritin Syrup 5mg/5cc QD dose for ages 2 years and above Or Oral non-sedating antihistamines Clarinex or Allegra as needed Preferred in patients where sedation or performance impairment caused by sedating antihistamines can interfere with work, learning, productivity, mental alertness or safety. Or Topical nasal antihistamine Astelin Clinical Note: Sedating antihistamines should be avoided in school children, elderly, and individuals who require mental acuity and psychomotor alertness for their occupations. Clinical Note: Add decongestant if congestion or blockage predominate. Avoid decongestant in patients with cardiovascular illnesses or other contraindications to pseudoephedrine Antihistamines Oral Systemic and topical antihistamines are considered a first line therapy for mild to moderate acute, occasional, or intermittent symptoms of seasonal or perennial allergic rhinitis. Antihistamines are not recommended for single agent treatment of severe persistent rhinitis unless symptoms persist with intranasal corticosteroid treatment. They reduce the symptoms of itching, sneezing, and rhinorrhea but they have only minimal effectiveness with nasal congestion. Because older first generation antihistamines are associated with sedation, which limits their use, second-generation nonsedating or less-sedating agents are preferred (American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Milwaukee: American Academy of Allergy, Asthma, and Immunology, 2000). Other side effects of mostly the first generation agents include psychomotor and cognitive impairment, confusion, irritability, and anticholinergic effects. Antihistamines and intranasal corticosteroids appear to have complementary mechanisms of action but clinical trials do not support their co-administration or benefit compared with intranasal corticosteroids alone (Howarth PH: Allergy 2000;(suppl 62):6-11). One of the major advantages of the use of antihistamines is the rapid onset of action. The onset of action of second generation antihistamines has been studied with the use of closed environmental chambers where subjects are exposed to an allergen. The onset of action and clinical relief of specific symptoms is recorded at specified time intervals usually 20 minutes for 4 to 12 hours. Generally, the onset of action for desloratadine, loratadine, fexofenadine, and cetirizine has been shown to be in the 1 to 3 hour range (Day JH: Ann Allergy Asthma Immunol 1997;79:533-540, Day JH: J Allergy Clin Immunol 1998;101:638-645, Horak F: Allergy 2000;55(suppl 63):279). Active treatment, placebo-controlled clinical efficacy and safety trial have generally demonstrated no significant clinical differences between desloratadine, loratadine, fexofenadine, and cetirizine. The only difference is that cetirizine is associated with a higher incidence of sedation and somnolence than that of desloratadine, loratadine, and fexofenadine (Zyrtec package insert). Cetirizine is not approved for use by the Federal Aviation Administration for pilot use. Patients should be counseled about the proper use of antihistamines. Adverse effects especially sedation with older antihistamines and cetirizine, should be reviewed. Patients should be warned about taking other central nervous system depressants and alcohol in combination with antihistamines. Patients should check with their pharmacist and read labels before taking nonprescription medications. Many cold products and sleep aids contain antihistamines. Patients should be instructed not to use more than one antihistamine at a time. Topical Antihistamines For seasonal allergic rhinitis and non-allergic vasomotor rhinitis, an intranasal antihistamine, azelastine (Astelin®), is available. Patients generally express a high degree of satisfaction with this product because it rapidly relieves symptoms (approximately 3 hours). This agent is appropriate as first line treatment for allergic rhinitis, and may have greater effects on nasal congestion than oral antihistamines (Newson-Smith G: Otorhinolaryngol 1997;254:236-241). Azelastine is absorbed when administered topically and therefore some drowsiness (reported at about 11.5%) may occur. Patients should be warned of this potential. Another commonly reported side effect is a bitter aftertaste (19.7%). The formulary coverage restrictions placed on non-sedating antihistamines in California Health Plans have not been placed on azelastine and this product has widespread formulary coverage. According to the ARIA guidelines, intranasal antihistamines are treatment options for patients with mild intermittent rhinitis, mild persistent rhinitis, and moderate-severe intermittent rhinitis. Intranasal antihistamines are only recommended in moderate-severe persistent rhinitis if symptoms persist after first line treatment with INCS. Decongestants Topical Topical decongestants are applied directly to swollen nasal mucosa via drops and sprays. There is little or no systemic absorption. These agents are very effective. Their availability over-the-counter leads to widespread use. Prolonged use of these agents for longer than 3 to 5 days can result in a condition known as rhinitis medicamentosa, or rebound vasodilation, with associated congestion. Patients may become dependent on these products with more use and less effect over time. Weaning patients from topical decongestants can be difficult. Abrupt cessation leads to rebound congestion. Sleeping may be difficult. A combination of nasal steroids, gradual dose frequency reduction, and dilution may be considered in the weaning effort. Systemic decongestants Oral decongestants are not as effective as topical decongestants on an immediate basis. They are longer lasting and do not cause local irritation. Also, rhinitis medicamentosa is not a problem. Pseudoephedrine is probably the safest systemic decongestant. The difference between doses that produce a measurable change in heart rate and blood pressure is narrow with 180mg per day showing little or no impact and 210-240mg per day raising both blood pressure and heart rate (Empey DE: Br J Clin Pharmacol 1980;9:351-358. Drew CDM: Br J Clin Pharmacol 1978;6:221-225). Pharmacists need to be aware that most studies of the impact of decongestants on blood pressure and heart rate were conducted in normotensive individuals and not patients with hypertension: therefore, caution should be used in patients on antihypertensive therapy. Inhaled Nasal Corticosteroids Inhaled nasal corticosteroids (INCS) are an excellent, most effective, and preferred first choice for managing both mild to severe persistent seasonal and perennial allergic rhinitis. INCS are effective in treating most of the major symptoms of allergic rhinitis, including sneezing, rhinorrhea, itching, and nasal congestion or blockage. INCS produce significantly greater reduction in total nasal symptom scores than oral sedating and non-sedating antihistamines, leukotriene receptor antagonists, the combination of antihistamine and leukotriene receptor antagonist, and topical antihistamines (Yanez A: Ann Allergy Asthma Immunol 2002;89:479-484, Nelson HS: J Allergy Clin Immunol 2003;111:S793-S798, Weiner JM: BMJ 1998;317:1624-1629, Stempel DA: Am J Managed Care 1998;4:89-96). All INCS formulations have been found to be effective and safe and to have significant effects on quality of life for patients with allergic rhinitis. There are some important differences that require special attention. One of the most important differences among the INCS is patient preference based on sensory attributes such as taste, smell, spray volume, irritation, etc. There have been many studies comparing patient preferences and the results are often confusing as most of these studies are sponsored by the manufacturer, are single dose or short duration, and do not assess clinical response as part of the overall satisfaction. In a recent survey, patients reported that they preferred a product with no odor or taste (Kaliner MA; Allergy Asthma Proc 2001;22(suppl 6):S11-S15). Similar results have been reported in other studies indicating that patients prefer odorless and tasteless INCS (Bachert C: Ann Allergy Asthma Immunol 2002;89:292-297, Shah SR: 58th Annual Meeting of the Am Acad of Allergy Asthma and Immunol; March 1-6, 2002 NY,NY abstract). Sensory attributes and patient preference of an INCS should be taken into account when prescribing an INCS but other factors should also be considered, including dose frequency, safety profile and cost. Another important consideration in selecting an INCS is safety. Most of the products have been determined to be safe at usual doses: however it is impossible to dismiss that prolonged use of INCS may result in systemic side effects such as hypothalamic-pituitary-axis (HPA) suppression. The clinical attributes of the INCS that impact the potential for systemic side effects include topical potency, lipophilicity, and absorption. Topical potency is usually determined by the degree of cutaneous vasoconstrictive activity from a skin model. The two most potent INCS are mometasone and fluticasone. The degree of vasoconstriction does not directly correlate with anti-inflammatory potency but does at least partially explain clinical efficacy (Mygind N: Clin Immunother 1996;5:122-136). Glucocorticoid receptor binding affinity is another measure of potency. In one study the ranking of binding affinity was mometasone > fluticasone > budesonide > triamcinolone > dexamethasone (Smith CL: Arzneimittelforschung/Drug Res 1998;48:956-960). Lipophilicity is another characteristic of INCS that influences their clinical pharmacologic actions. Highly lipophilic agents are more likely to be absorbed faster and to a greater degree into the nasal mucosa. This enhances the ability of the agent to reach the glucocorticoid receptor. The rank order of INCS lipophilicity is mometasone > fluticasone > beclomethasone > budesonide > triamcinolone > flunisolide (Johnson M: J Allergy Clin Immunol 1998;101:S434-S439). Systemic absorption is another concern and can be broken down into two aspects: amount of drug absorbed through the nasal mucosa and fraction of the dose that is swallowed and absorbed in the gastrointestinal tract. Once again, mometasone followed by fluticasone have the most favorable systemic absorption profile with mometasone at 0.1% and fluticasone at < 2%. In addition, any mometasone or fluticasone that is swallowed is not likely to be absorbed because of the high lipophilicity (Szelfler SJ: J Allergy Clin Immunol 2001;108:S26-S31). Other INCS have oral bioavailabilities between 20% and 50%. The effects of inhaled corticosteroid treatment on growth of asthmatic children prompted a similar study of the impact of INCS on growth in children with perennial allergic rhinitis. A statistically significant reduction in growth velocity was reported in a 12-month study of young children (aged 6-9 years) when treated with 336 ug/day of beclomethasone dipropionate (Rachelefsky GS: J Allergy Clin Immunol 1998;101:S236). The treated group had slower growth rates of 0.013 cm/day or 5 cm/year versus the placebo group at 0.017cm/day or 5.9 cm/year. Studies of other products and their impact on growth are limited. One other product in particular has undergone additional study to determine safety in children (Schenkel EJ: Pediatrics (on line) February 1, 2000). Mometasone (Nasonex®) nasal spray has been studied in children and has been shown with stadiometric analysis not to impact child growth. Other agents have also been studied but not with the more sensitive stadiometry methods. Why is this important? Because many parents are concerned about the administration of corticosteroids to their children and the potential impact on stature. This is especially crucial in children with asthma and allergic rhinitis who may receive both an inhaled and nasal corticosteroid to treat their disease. INCS frequently cause nasal irritation. Local side effects of dryness, burning and stinging, and sneezing, along with headache and epistaxis occur in about 5-10% of patients and are consistent among the different product formulations. Pharmacists can help patients avoid septal perforation, which is rare but does occur, by counseling patients on appropriate administration techniques. Antileukotriene Therapy The FDA has recently approved the use of montelukast (Singulair®) for the treatment of seasonal allergic rhinitis. Several studies have evaluated the effectiveness of montelukast in the treatment of allergic rhinitis. In one study, montelukast 10mg, loratadine 10mg, and placebo were compared in a group of patients with allergic rhinitis (Phillip G: Clin Exp Allergy 2002;32:1020-1028). The results indicated that montelukast and loratadine were significantly more effective than placebo but montelukast was not better than loratadine. In fact, net treatment scores for montelukast were less than loratadine. In a recent review of articles and abstracts on the treatment of allergic rhinitis, the clinical efficacy of leukotriene antagonists was compared to that of INCS and non-sedating antihistamines (Nathan RA: Ann Allergy Asthma Immunol 2003;90:182-191). This review did not find many studies to support the wide use of leukotriene receptor antagonists in allergic rhinitis. The review determined that leukotriene receptor antagonists are sometimes more effective than placebo; they are no more effective than non-sedating antihistamines, and are less effective than intranasal corticosteroids in the treatment of allergic rhinitis. Given the higher cost of montelukast and its limited and as yet unproven clinical efficacy, it would seem prudent to consider its use as only a second line agent. Certainly further studies are needed to determine whether long-term therapy with leukotriene receptor antagonists results in better control of allergic rhinitis than alternative therapies. Immunotherapy Randomized, double-blind, placebo-controlled clinical trials have demonstrated the clinical efficacy of allergen-specific immunotherapy in the treatment of allergic rhinitis. Patients who have IgE antibodies to specific allergens should be considered for immunotherapy. Immunotherapy is the only treatment that has the chance to alter the course of allergic rhinitis. Summary Treatment of allergic rhinitis should be directed toward avoidance, medications, and immunotherapy. Use of medications should be tailored to both frequency and severity of symptoms. Generally, INCS are considered first line agents for the treatment of seasonal and perennial allergic rhinitis symptoms. EDITOR: Randall Seifert, Pharm.D EDITORIAL ADVISORY BOARD: Kurt Ransohoff, M.D. Sansum-Santa Barbara Medical Foundation Clinic; Gary Proffett, M.D. Seaview IPA; Robert Finkelstein, M.D. Facey Medical Group; Eileen Goodis, Pharm.D, Home Pharmacy Inc.; Angelo Giambrone, Pharm.D Prescription Solutions; Mel Baron, Pharm.D USC School of Pharmacy, and Kathy Johnson, Pharm.D, USC School of Pharmacy This article is underwritten by an educational grant from Schering–Plough (A Nonprofit Corporation) 701 North Brand Blvd., Suite 380 Glendale, CA 91203 Phone 818.549.2285 MISSION STATEMENT The Institute for Community Pharmacy (ICP) is a non-profit organization committed to advancing community pharmacy through continuing education, quality initiatives, and relationship building.