Review of H1 Antihistamines in the Treatment of ... - Ob.Gyn. News

CONTINUING MEDICAL EDUCATIONReview of H 1 Antihistamines in theTreatment of Chronic Idiopathic UrticariaEugene Monroe, MDGOALTo understand chronic idiopathic urticaria (CIU) to better manage patients with the conditionOBJECTIVESUpon completion of this activity, dermatologists and general practitioners should be able to:1. Describe the effect of CIU on patient quality of life.2. Discuss antihistamine use in the treatment of CIU.3. Explain the anti-inflammatory properties of antihistamines.CME Test on page 104.This article has been peer reviewed andapproved by Michael Fisher, MD, Professor ofMedicine, Albert Einstein College of Medicine.Review date: July 2005.This activity has been planned and implementedin accordance with the Essential Areas and Policiesof the Accreditation Council for Continuing MedicalEducation through the joint sponsorship of AlbertEinstein College of Medicine and QuadrantHealthCom, Inc. Albert Einstein College of Medicineis accredited by the ACCME to provide continuingmedical education for physicians.Albert Einstein College of Medicine designatesthis educational activity for a maximum of 1category 1 credit toward the AMA Physician’sRecognition Award. Each physician shouldclaim only that credit that he/she actually spentin the activity.This activity has been planned and produced inaccordance with ACCME Essentials.Dr. Monroe is in the speakers program and has been a clinical investigator for Sanofi-Aventis and Schering-Plough Corporation. The author discusses off-label use for antihistamines, antileukotrienes, corticosteroids,cyclosporine, doxepin, and tricyclic antidepressants. Dr. Fisher reports no conflict of interest.Chronic idiopathic urticaria (CIU) can have aprofound effect on patient quality of life (QOL).Ideally, any therapy used to treat CIU should beeffective across a wide range of doses withoutcausing unwanted side effects; a wide therapeuticwindow allows the physician to tailor treatmentAccepted for publication April 12, 2005.Dr. Monroe is President, Department of Dermatology, AdvancedHealthcare, Milwaukee, Wisconsin.Reprints: Eugene Monroe, MD, Department of Dermatology,Advanced Healthcare, Milwaukee, WI 53209-4590(e-mail: emonroe@ah.com).to the individual. Oral H 1antihistamines are themainstay of therapy for CIU, but agents withinthis class diverge in their individual therapeuticindices. The literature was reviewed to comparethe currently available oral H 1antihistaminesregarding their efficacy and safety at a widerange of doses. If sedation and cognitive impairmentare considered relevant to treatment selectiondue to their effect on QOL and safety, thennewer-generation agents should be selectedover older-generation antihistamines. There arefew well-controlled clinical studies in whichnewer-generation agents have been directly118 CUTIS ®

Antihistamines for CIUcompared. Moreover, there are no evidencebaseddata demonstrating statistical superiorityof one newer-generation agent over another inthe treatment of CIU. However, of the neweragents, those that are labelled nonsedating atrecommended doses (fexofenadine, loratadine,and desloratadine) should be selected overcetirizine. In cases where the physician judgesthat a higher-than-recommended dose should beprescribed, or when the patient is likely to take ahigher dose, the relative safety profile of theseagents demands detailed consideration.Cutis. 2005;76:118–126.How idiopathic is chronic idiopathic urticaria(CIU)? With the fast pace of scientific andmedical discovery, it is anomalous that diseaseswith no known cause remain. However,despite the fact that CIU is less well understoodthan many other diseases, recent findings havepartially illuminated this condition’s etiology.At least 2 subgroups of patients with CIU exist.One group is composed of 30% to 50% of patientswith CIU with autoimmune chronic urticariacaused by autoantibodies against either the highaffinityimmunoglobulin E (IgE) receptor FcRI or,less commonly, IgE. 1,2 Patients in this subgrouphave an increased likelihood of thyroid autoimmunity;thyroid autoantibodies, Hashimoto thyroiditis,and Graves disease are recognized as beingassociated with CIU. 3 Indeed, 27% of patientswith CIU have high-titre antithyroglobulin,antithyroid peroxidase autoantibodies, or both,and 19% have abnormal thyroid function. 3 However,the remaining 50% to 70% of patients withCIU are truly idiopathic, because there is noknown cause for the disease. 1In keeping with the illusive nature of CIU, theprevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to20% of the US population experience at least oneepisode of urticaria in their lifetime, and up to 3%of the population are diagnosed with CIU. 5,6 Interestingly,middle-aged women are more likely toexperience the condition than other groups 7 ; also,women are approximately 3 times more likely thanmen to acquire any autoimmune disease duringtheir lifetime, 8 supporting the notion that CIU isoften an autoimmune disease.Quality of LifeThe impact of a disease extends beyond physical signsand symptoms; health-related quality of life (QOL)also should play a pivotal role in the evaluation ofthe effect of a disease or its treatment. Thisparameter is particularly pertinent to CIU, asevidenced by O’Donnell et al 9 whose analysis of adisease-specific, purpose-designed questionnaireand the Nottingham Health Profile demonstratedthat patients with chronic urticaria experiencedconsiderable disability, handicap, and reducedQOL. Part 1 of the health profile showed thatpatients were restricted in areas of mobility,sleep, and energy and experienced pain, socialisolation, and altered emotional reactions. Part 2showed that patients experienced problems inrelation to work, home management, social life,relationships, sex life, hobbies, and holidays.Interestingly, patients in this survey had almostidentical scores for part 1 of the health profile asdid patients with coronary artery disease; bothgroups experienced lack of energy, feelings ofsocial isolation, and emotional upset. 9Perhaps because skin diseases are so visible andthus potentially stigmatizing, dermatology patientscan be impacted significantly in terms of QOL;however, the effect of CIU appears to be particularlyacute. Using the validated Dermatology LifeQuality Index (DLQI), a survey of 170 consecutivepatients had results that showed that patients withCIU experienced greater QOL impairment thanoutpatients with either psoriasis, acne, or vitiligoand experienced a comparable level of impairmentto patients with severe atopic dermatitis. 10 Becauseof CIU’s devastating effect on health-related QOLand the discomfort of CIU, appropriate treatmentselection is crucial. The ideal treatment for CIUwould not only rid the patient of the wheals,edema, and pruritus that characterize the conditionbut also improve QOL. This review outlines thetreatment options available, focusing on oral H 1antihistamines, and offers a means of differentiatingthis class of agent.Antihistamines in the Treatment of CIUIt is well established that elevated tissue levels ofhistamine are found in the skin of patients withdifferent forms of chronic urticaria. 11-13 Althoughmore subclasses of histamine receptors have beenidentified, those initially isolated—H 1and H 2—are involved in the cutaneous responses seen inurticaria. Specifically, the binding of histamine tothe H 1receptor causes erythema (by vasodilation),edema (by increasing vascular permeability), anditching. The same responses, with the exception ofitching, are caused by histamine binding to the H 2receptor. In 30% to 50% of patients diagnosed withCIU, histamine release from mast cells leads towheal formation because of an autoimmune process.VOLUME 76, AUGUST 2005 119

Antihistamines for CIUIn contrast, patients with CIU without this autoimmuneresponse experience the same effects ofmast cell degranulation and subsequent release ofhistamine by a process yet to be elucidated.The sentinel involvement of histamine in CIUis, therefore, unequivocal; irrespective of etiology,the appropriate use of H 1antihistamines—whichstabilize an active conformation of the H 1receptorand thus prevent activation by histamine—remainsthe basis of treatment. 14 However, for patientsunresponsive to conventional H 1-antihistaminemonotherapy, adjunctive treatments often are prescribedincluding a combination of H 1antihistamines(either 2 different newer-generation agents concurrentlyor a newer-generation agent plus a firstgenerationagent at night), H 2antihistamines,tricyclic antidepressants (principally doxepin),antileukotriene therapy, and intermittent pulses ofcorticosteroids. 15 In the event of inadequate symptomcontrol after these therapies have beenexplored, immunomodulatory agents such ascyclosporine have been used to treat patientsrefractory to conventional therapy. 14The method of activity for the adjunctive treatmentsis based on the following approaches: blockingH 1and H 2receptors, blocking nonhistaminemediators of urticaria, and blocking the cellular andinflammatory components of the urticarial reaction.In summary, because H 1antihistamines are first-linetherapy for CIU, and for many patients remain theonly option available, the selection of the optimalantihistamine is of vital importance.Selection of AntihistaminesThe first antihistamine was developed in 1937;in the 1940s, phenbenzamine became the firstcommercially available antihistamine, followed bysimilar H 1-receptor antagonists such as chlorpheniramine,brompheniramine, and diphenhydramine.Despite its relative antiquity, diphenhydramineremains the most widely used antihistamine in theUnited States. 16 These first-generation H 1-receptorantagonists, though effective in the treatment ofurticaria and allergic rhinitis, were shown to causeundesired side effects for 2 distinct reasons: theirlack of selectivity for the H 1receptor and theirpropensity to cross the blood-brain barrier and affectthe central nervous system. 17As a result of their lack of selectivity, oldergenerationagents cause anticholinergic effects suchas dry mouth, headache, and urinary retention. 18-20Furthermore, at supraclinical doses, some antihistaminesare toxic 16 and have been shown to causesinus tachycardia. 21 Children have been known toexperience severe toxic reactions and even deathfollowing overdose of older-generation antihistaminesbecause of the drug’s lack of selectivity. 22-25Because older-generation antihistamines canbind to H 1receptors in the brain and histamine inthe brain plays a role in central nervous systemarousal and alertness, these agents also are associatedwith sedation and cognitive impairment (eg,impaired sensorimotor coordination and decreases inattention span, memory function, ability to processinformation, and psychomotor performance 16,26,27 ).The binding of first-generation antihistamines tocerebral H 1receptors has been demonstrated inmany studies employing objective psychometric testsand also by the relatively new technique of positronemission tomographic imaging. 28-30Newer-Generation AntihistaminesNewer-generation antihistamines were developed inthe early 1980s with the aim of being more specificfor the H 1receptor, as well as of overcoming theadverse events observed with older agents. As testamentto achieving this goal, allergists agree thatnewer-generation antihistamines are preferred tofirst-generation agents because of their more favorableefficacy:safety ratio. 16,18 Although there is nosuch formal consensus among dermatologists andthose specifically treating CIU, it is likely the samelogic would apply if equivalent efficacy between oldand new antihistamines can be established for CIU.This review explores the newer-generation antihistaminesavailable in the United States for thetreatment of CIU: fexofenadine, loratadine, desloratadine,and cetirizine. An evidence-based analysisof the efficacy of these agents and an analysis of thetherapeutic window of these antihistamines, withparticular focus on their sedation and cognitiveimpairment potential, are emphasized (Table).Efficacy of Newer-Generation AntihistaminesNumerous randomized double-blind clinical studieshave demonstrated the efficacy of fexofenadine, 31-34loratadine, 35,36 desloratadine, 37,38 and cetirizine 39,40 inrelieving the symptoms of CIU.Fexofenadine—The safety and efficacy of variousdoses of fexofenadine at relieving the symptomsof CIU has been established in several largerandomized controlled clinical trials. Two similarCIU studies investigated the efficacy of fexofenadineHCl using doses of 20, 60, 120, and 240 mgtwice daily (BID). In both studies, doses of 60 mgor more BID were shown to reduce severity ofpruritus, number of wheals, and interference withsleep and normal daily activities compared withplacebo. 33,34 Furthermore, studies in Japanese andThai patients have indicated that the effectiveness120 CUTIS ®

Antihistamines for CIUH 1Antihistamines in Chronic Idiopathic Urticaria: Efficacy and Safety Comparison*Drowsiness Drowsiness ( Impairment Impairment (Anticholinergic (Recommended Recommended (Recommended RecommendedAntihistamine Efficacy Effect Dose) Dose) Dose) Dose)Cetirizine 3 0 1 1 1 1Chlorpheniramine 2/3 3 2 3 2 3Desloratadine 3 0 0 1 0 1Diphenhydramine 3 3 3 3 3 3Fexofenadine 3 0 0 0 0 0Hydroxyzine 3 3 3 3 3 3Loratadine 3 0 0 1 0 1*0 indicates none; 1, mild; 2, moderate; 3, strong.of fexofenadine 60 mg BID is not limited byethnicity or genotype. 41,42Although many studies have examined some QOLparameters as secondary endpoints as a componentof efficacy studies, fexofenadine has been studiedusing the validated DLQI and Work Productivityand Activity Impairment questionnaires. 43 Twoidentically designed 4-week, multicenter, randomized,double-blind, placebo-controlled, parallelgrouptrials examined the effects of 60 mg BID onpatients aged 12 to 65 years with moderate tosevere CIU. Fexofenadine treatment significantlyimproved overall DLQI score compared withplacebo (P≤.0002), and also significantly increasedwork productivity (P≤.014). In addition, a trendtoward increased classroom productivity and significantimprovements in 5 of the 6 individual DLQIdomains were observed. 43The efficacy and safety of a range of once-daily(QD) doses of fexofenadine have been evaluatedin a large, multicenter, double-blind, placebocontrolled,parallel-group, dose-ranging study. 31Adults (N222) were randomized to receive eitherfexofenadine HCl 60, 120, 180, or 240 mg QD orplacebo QD for 6 weeks. The combined fexofenadinegroups showed a significant reduction in meantotal symptom score (pruritus score and number ofwheals) compared with placebo (P.0019). Thestudy suggested that 180 mg QD is the optimal dosefor the treatment of CIU because this dose alonesignificantly reduced the number of wheals comparedwith placebo (P.0064) and significantlyimproved mean total symptom score consistentlyover the 6-week study period (P.05). 31 Supportingthe efficacy of this once-daily dose, a recentdouble-blind placebo-controlled study of fexofenadineHCl 180 mg QD was shown to produce a beneficialeffect on urticaria. 32Loratadine—The relative efficacy of loratadineand the first-generation antihistamine hydroxyzinehas been established in a large 4-week (optional12-week) trial comparing the 2 compounds withplacebo in 172 patients with CIU. Patients wererandomized to receive either: 10 mg loratadine QDand placebo BID; hydroxyzine 3 times daily; orplacebo 3 times daily. As measured by all efficacyevaluations (physician and patient evaluations ofthe effect of treatment at each visit plus patientdaily diary cards), loratadine and hydroxyzine werefound to be more effective than placebo and clinicallycomparable to each other. 35In the only placebo-controlled comparativestudy between 2 newer-generation antihistamines inthe treatment of CIU, Guerra et al 44 showed thatloratadine was more effective than cetirizine in someaspects of controlling the symptoms of CIU. In thisdouble-blind study, 116 patients with CIU wererandomly assigned loratadine 10 mg, cetirizine 10 mg,or placebo QD for 28 days. Both active drugs significantlyreduced global clinical symptoms (P.05),but loratadine was more rapid in developing itsactivity than cetirizine (P.01 at day 3) andalso appeared to be safer when the frequency oftreatment-emergent side effects were compared. 44VOLUME 76, AUGUST 2005 121

Antihistamines for CIUDesloratadine—Desloratadine is the major activemetabolite of loratadine, which has been availablein the United States since 2002 for the treatment ofCIU. The efficacy of the drug has been evaluated in2 major randomized controlled clinical trials. 37,38Ring et al 37 reported that desloratadine exhibitedsuperior efficacy compared with placebo in amulticenter, randomized, double-blind trial of190 patients with a history of CIU. Patients wereassigned to receive either desloratadine 5 mg QDor placebo QD for 6 weeks. The active treatmentwas superior to placebo at reducing pruritus andoverall symptoms after the first dose and throughoutthe 6-week study. 37 Similarly, therapeuticresponse and global CIU status, as well as QOLmeasures such as interference with sleep, wereimproved with desloratadine compared withplacebo throughout the study period. 37 Using thesame dose (5 mg QD), a further 6-week placebocontrolledstudy of desloratadine indicated theeffectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIUsymptom score was significantly improved comparedwith placebo, as were the individual scores ofpruritus, number of hives, and the size of the largesthive. Interference with sleep was reduced and performanceof daily activities was improved withdesloratadine. These statistically and clinically significantimprovements were seen within the first24 hours of treatment and were sustained throughoutthe 6-week treatment period. 38Cetirizine—As with loratadine, cetirizine hasbeen shown to be as effective as first-generationhydroxyzine at relieving the symptoms of CIU. 40For example, a 4-week, multicenter, randomized,double-blind, double-dummy trial investigated theefficacy and safety of cetirizine 10 mg QD andhydroxyzine 25 mg 3 times daily compared withplacebo in patients with CIU. Patients in the cetirizineand hydroxyzine groups showed significantreductions during weeks 1, 2, 3, and 4 in the numberand size of lesions and in the severity of prurituscompared with patients who received placebo.In addition, physician and patient evaluations atthe end of week 4 revealed an improvement inurticarial symptoms for the cetirizine and hydroxyzinegroups compared with the placebo group. 40All 4 newer-generation H 1antihistamines (fexofenadine,loratadine, desloratadine, and cetirizine)have been shown to be superior to placebo at treatingthe symptoms of CIU, and both loratadine andcetirizine have been proven to be as effective asfirst-generation hydroxyzine. 35,40 Although no trialshave evaluated fexofenadine and desloratadine comparedwith hydroxyzine, comparisons demonstratingequivalence have been made with their parent compounds(loratadine 35 and terfenadine 45 ).There are few controlled studies in whichnewer-generation antihistamines have been directlycompared, and there is no evidence-based datademonstrating statistical superiority of one secondgenerationagent over another in the treatment ofCIU. For example, although a recent trial comparedthe efficacy of cetirizine with fexofenadine,the results are weakened by the study design.Patients with CIU were randomized to eithercetirizine 10 mg (n52) or fexofenadine 180 mg(n45); at 28 days, 51.9% (27) and 4.4% (2) ofcetirizine and fexofenadine patients, respectively,were symptom free (P.00001), while partialimprovement was experienced by 36.5% (19) ofcetirizine patients and 42.2% (19) of fexofenadinepatients. 46 However, there was no control group,baseline symptom severity data were not provided,and the authors did not describe how thepatients’ symptoms were assessed. 46 Therefore, adefinitive assessment of the relative efficacy ofnewer-generation antihistamines cannot be achievedby reviewing published trials alone.Anti-inflammatory PropertiesDue to the absence of well-designed placebocontrolledcomparisons of newer-generation antihistamines,other properties have been examinedto aid treatment comparisons. For example, it hasbeen suggested that some H 1-receptor antagonistsmay achieve anti-inflammatory effects in a clinicalcontext, which could prove advantageous in thetreatment of CIU because the disease is characterizedby tissue inflammation. 47To investigate the anti-inflammatory activity offexofenadine, an immunohistochemical evaluationof the agent was undertaken in patients with CIU. 48Twenty patients received fexofenadine HCl 180 mgQD for 4 weeks; the expression of adhesionmolecules, mast cell proteases, and proinflammatorycytokines were evaluated before and after treatment,as were the patients’ assessments of urticarial symptoms.After treatment with fexofenadine, significantdecreases in the expression of endothelial leukocyteadhesion molecule-1 (P.02), vascular cell adhesionmolecule-1 (P.04), and tryptase (P.04) wereobserved, confirming the hypothesis that fexofenadinehas some anti-inflammatory properties.This study in humans must be put into contextwith the numerous in vitro, ex vivo, and animalstudies that have been conducted in this area. A reviewof such data suggests that all newer-generationantihistamines inhibit the release or generation ofmultiple inflammatory mediators, including IL-4,122 CUTIS ®

Antihistamines for CIUIL-6, IL-8, IL-13, prostaglandin D 3, leukotriene C,tryptase, histamine, and the tumor necrosis factor–induced chemokine regulated upon activationnormal T cell expressed and secreted, in additionto eosinophil chemotaxis and adhesion molecules. 47For example, both loratadine and desloratadine(10 mol/L) significantly inhibited the expressionof intercellular adhesion molecule-1 and class IIHLA antigen (HLA-DE) in nasal epithelial cells invitro. 49 However, many of these anti-inflammatoryeffects have only been observed at high drugconcentrations. 47 For example, an in vitro studyof cetirizine assessing the inhibition of IL-5–dependent eosinophil survival revealed a concentrationof 100 mol/L was required to achievesignificant inhibition—much higher than thatused clinically. 47,50Clearly, if clinical anti-inflammatory effectsnecessitate doses higher than those recommendedfor allergic diseases, drugs that can be used at higherdoses without causing unwanted side effects such assedation and cognitive impairment may be of thegreatest utility in the treatment of CIU. This is aparticularly pertinent point because patients withCIU may be prescribed much higher doses than recommendedto manage symptoms effectively. 17The Therapeutic Window—Because of the lack ofrigorously designed clinical trials comparing the efficacyof second-generation antihistamines and theputative anti-inflammatory activities of these agentsthat may occur at higher-than-recommendeddosing levels, the relative safety of agents maydirect the selection of the optimum antihistaminefor the treatment of CIU. Ideally, an agent wouldbe effective at a wide range of doses withoutcausing unwanted side effects. This is because awide therapeutic window permits the physician tooptimize treatment to the individual. The safety ofthe newer-generation antihistamines has beenassessed in numerous clinical trials, usually assecondary analyses to efficacy parameters; indeed,all of the efficacy studies described here indicateda good safety and tolerability profile for each ofthe antihistamines.Clinical trials, however, do not always reflect thereality of clinical practice. Patients taking antihistaminesfrequently overcomply with their medication,51 particularly if they do not experienceimmediate relief. Furthermore, as previously mentioned,it is occasionally necessary for dermatologiststo prescribe high doses of antihistamines for patientswho do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of thedifferent antihistamines at high doses to obtain atrue picture of how drugs may be affecting patients.Sedation and Impairment—A number of studiesusing objective psychometric tests have indicatedthat newer-generation antihistamines generallyhave better sedative profiles than first-generationagents; however, at higher doses, sedation andimpairment become evident.Two meta-analyses of published data on antihistaminesreport that newer drugs had lowerimpairment/nonimpairment ratios than olderagents. 28,29 That is, proportionally more studies indicatednonimpairment versus impairment with thenewer agents compared with their predecessors.However, the same meta-analyses revealed thatboth loratadine and cetirizine were associated withsedation/impairment in a number of tests, oftenwhen they were used at higher-than-recommendeddoses. In contrast, fexofenadine, even at doses of upto 360 mg, was not associated with any sedation orimpairment and had an impairment:nonimpairmentratio of zero. 28,29A study by Mann et al 52 corroborates the findingthat different newer-generation antihistamines havethe potential to cause sedation, with fexofenadinebeing the least likely of those studied to do so. Thisprescription-event monitoring study showed thatthe odds ratios for the incidence of sedation were0.63 for fexofenadine and 5.53 for cetirizine comparedwith loratadine. 52 Higher-than-recommendeddoses of loratadine 53 and desloratadine 54 also cancause sedation.A recent approach to the question of bloodbrainbarrier penetration involves the use ofpositron emission tomography. This technique hasbeen used to study the binding of antihistamines tocerebral H 1receptors. Tashiro et al 30 used positronemission tomographic imaging to compare fexofenadinewith cetirizine by examining relative H 1receptor occupancy in the brain. Quantitativeanalysis showed that fexofenadine did not occupyH 1receptors in the cerebral cortex, while cetirizineoccupied between 20% to 50% of the H 1receptors,depending on the brain region. 30 These findingssupport evidence from comparative trials thatindicate that although cetirizine is less sedatingthan older antihistamines, it causes more sedationand impairment of performance than other secondgenerationantihistamines. As a result, the US Foodand Drug Administration has classified cetirizine assedating rather than nonsedating, and the productcarries the full sedation precaution.CommentAntihistamines can be used effectively to controlthe symptoms of CIU; newer-generation antihistamineshave been shown to be as effective asVOLUME 76, AUGUST 2005 123

Antihistamines for CIUtheir predecessors at relieving patients of theirsymptoms 35,40 and improving their QOL. 43 However,there is a paucity of well-designed placebo-controlledcomparative clinical trials; the data available indicatethat agents are effective and safe, but they donot provide a means to assess which agent is thesafest and most effective. Instead, we must examinealternative sources of evidence to help us select theoptimum antihistamine for the treatment of CIU.Evidence from pharmacologic studies indicatesthat newer agents demonstrate some antiinflammatoryactivity, which could provideadditional therapeutic benefit. However, thesestudies have largely been limited to in vitro testsand animal modeling and do not yet provide themeans to differentiate agents.Newer-generation antihistamines vary in theirpropensity to cause sedation and cognitive impairment,with cetirizine representing the most impairingof the class, as recognized by its sedating descriptionby the US Food and Drug Administration. At recommendeddoses, fexofenadine, loratadine, anddesloratadine have not been found to cause significantimpairment and are labeled as nonsedating bythe US Food and Drug Administration. However,patients with urticaria are known to take aboverecommendeddoses 51 and physicians occasionallyprescribe off-label doses to achieve the desired levelof symptom control. The risk of sedation caused bythese 2 factors should be considered in practicewhen selecting an antihistamine.Sedation and impairment affect QOL and manifestas decreased classroom learning ability anddecreased work productivity. 28 Furthermore, it hasbeen suggested that cerebral H 1-receptor blockade isassociated with falls in the elderly and cognitive slowing,and is a contributing factor in traffic accidents. 27ConclusionIn controlled clinical studies of CIU, the secondgenerationH 1-antihistamines have been proven tobe clinically comparable to the most potent of thefirst-generation antihistamines, such as hydroxyzine.Clinical studies comparing these agents arefew and have shown no statistically significant differencesin efficacy.If sedation and cognitive impairment are to beconsidered relevant to the choice of therapy for CIUbecause of their impact on QOL and safety, thennewer-generation agents should be selected overolder-generation antihistamines. 37,40 Furthermore, ofthe new agents, those that are labeled nonsedatingat recommended doses (fexofenadine, loratadine,and desloratadine) should be selected over cetirizine.However, in cases where the physician judgesthat a higher-than-recommended dose should beprescribed or when the patient is likely to take ahigher dose, fexofenadine should be considered. Inaddition to its proven efficacy in treating the symptomsof CIU, 31,33,34 fexofenadine is the only antihistaminethat is nonsedating, even at doses 2 to4 times above the recommended levels.REFERENCES1. Greaves MW. Chronic idiopathic urticaria. Curr OpinAllergy Clin Immunol. 2003;3:363-368.2. Hide M, Francis DM, Grattan CE, et al. Autoantibodiesagainst the high-affinity IgE receptor as a cause of histaminerelease in chronic urticaria. N Engl J Med.1993;329:1599-1604.3. Kaplan AP, Finn AF Jr. Pathogenesis of chronic uticaria.Can J Allergy Clin Immunol. 1999;4:286-292.4. Greaves MW, O’Donnell BF, Winkelmann RK. Chronicurticaria—evidence for autoimmunity. Allergy Clin ImmunolNews. 1995;7:36-38.5. Barnetson R. Allergy and the Skin. Allergy Immunologicaland Clinical Aspects. Hoboken, NJ: John Wiley andSons; 1994.6. Mathews KP. The urticarias—current concepts in pathogenesisand treatment. Drugs. 1985;30:552-560.7. Sibbald R, Cheema A, Lozinski A, et al. 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