brompheniramine, terfenadine, and placebo in allergic rhinitis

Brompheniramine, terfenadine, and placebo inallergic rhinitisGerald L Klein, MD*; Thomas Littlejohn, III, MD**; Earle A Lockhart, MD†; andSandy A Furey, PhD, MD†

Background: Second-generation antihistamines, reported to lack central nervoussystem depressant activity, may be considered to have a clinical advantage overtraditional antihistamines.Objective: To compare the effectiveness, at recommended doses, of an extended-

release formulation of nonprescription brompheniramine and prescription terfena-dine in the treatment of allergic rhinitis.Methods: This was a double-blind, randomized, placebo-controlled, multicenter,

parallel study. Subjects with symptoms of allergic rhinitis received bromphenira-mine 12 mg (n � 96), terfenadine 60 mg (n � 96), or placebo (n � 95) twice dailyfor 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, theinvestigator assessed symptom severity (ie, rhinorrhea; sneezing; nasal blockage;pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). Theinvestigator and the subject each completed a global efficacy evaluation, andsubjects were interviewed regarding the occurrence of adverse experiences. Symp-toms were analyzed as summed severity scores for (1) all symptoms and (2) for thesymptom cluster of rhinorrhea, sneezing, and nasal blockage.Results: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine

was significantly better (P � .05) than terfenadine and placebo for both sets ofsummed symptom scores and for both global assessments. Terfenadine was signif-icantly better (P � .05) than placebo on the physician’s global at day 14. Centralnervous system-related complaints were the most frequently reported adverse ex-periences among all three groups; somnolence was reported most frequently bybrompheniramine-treated subjects.Conclusion: A nonprescription, extended-release formulation of bromphenira-

mine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitisthan terfenadine, 60 mg bid.

Ann Allergy Asthma Immunol 1996;77:365–70.

INTRODUCTIONAllergic rhinitis is the most commonreaction to antigen stimulation involv-ing histamine release. Up to 22% ofthe US population is affected by a va-riety of plant and tree pollen on a sea-sonal basis, while a lesser percentagesuffers throughout the year because of

house dust, molds, and animal dan-der.1–3 Allergic rhinitis manifests itselfas a complex of symptoms that caninclude itching, sneezing, tearing, andnasal discharge. For decades, antihis-tamines have been the mainstay oftreatment; many are available withouta prescription. More recently, the useof “second-generation” H1-receptorantagonists has grown rapidly. Unlikethe first-generation antihistamines,which can sometimes be associatedwith central nervous system effects,4–5the newer H1 antagonists are reportedto be largely devoid of central nervoussystem depressant activity and, thus,may be considered to have a clinicaladvantage.6–8

Brompheniramine, a classic antihis-tamine, has been available for morethan 30 years as a nonprescriptionmedication for the relief of the symp-toms of allergic rhinitis. The effective-ness of brompheniramine has beendemonstrated in clinical trials and, incomparative studies, was found tohave a lower frequency of adverse ef-fects than other conventional antihista-mines.9–12 Terfenadine, the first nonse-dating antihistamine approved for usein the United States, has also beenshown in clinical trials to be effectivein providing symptom relief and it isreported to have a frequency of seda-tion comparable to placebo.13–15To our knowledge, these two medi-

cations have not been previously com-pared in a randomized, double-blind,placebo-controlled trial. The purposeof this study was to evaluate the effectsof treatment with standard recom-mended doses of an extended-releaseformulation of nonprescription brom-pheniramine and prescription terfena-dine in subjects with symptoms of al-lergic rhinitis.

MATERIALS AND METHODSSubjectsThe study population comprised adultmen and women, 15 years of age orover, with a history of allergic rhinitis.All presented with symptoms, had cor-roborating evidence of nasal mucosalchanges consistent with exposure to anantigen (ie, pallor, injection, edema),and positive skin tests to at least oneallergen. Those who had taken astem-izole within 30 days of the study, al-lergy medication within 72 hours, oran antihistamine within 24 hours werenot eligible. Women who were preg-nant, nursing, or at risk for pregnancy

Presented in part at the American Societyfor Clinical Pharmacology and Therapeutics(ASCPT) Ninety-Sixth Annual Meeting, San Di-ego, CA, March 15–17, 1995.Financial support for this research provided

by Whitehall-Robins Healthcare, Madison, NJ.Received for publication March 18, 1996.Accepted for publication in revised form June

6, 1996.

VOLUME 77, NOVEMBER, 1996 365

were also not eligible. Other reasonsfor exclusion were any medical condi-tion or use of any treatment that wouldinterfere with the interpretation ofstudy results, or contraindication to an-tihistamine use.

ProceduresThis was a double-blind, placebo-con-trolled, parallel-group, multicenterstudy. The study was conducted at twosites in California and one in NorthCarolina; subjects participated on anoutpatient basis. The study protocol re-ceived Institutional Review Board Ap-proval. All subjects, and a parent orguardian where appropriate, signed aninformed consent document prior totreatment.At the first visit, subjects provided

medical and allergy histories and un-derwent brief physical examinations,with particular emphasis on the eyes,nose, and throat to confirm the pres-ence of allergic rhinitis. The physicianevaluated the subject for the specificsymptoms of rhinorrhea; sneezing; na-sal blockage; pruritus of the eyes,nose,1 or pharynx; excessive lacrima-tion; and postnasal drip. The severityof each symptom was rated on a5-point scale as follows: 0 � none,1 � mild, 2 � moderate, 3 � severe,4 � very severe. To qualify for ran-domization, two or more of the symp-toms had to be at least moderate inseverity (a score of 2 or higher) and atleast one of these two symptoms had toinclude rhinorrhea, sneezing, nasalblockage, or postnasal drip.Subjects received brompheniramine

(12 mg) in an extended-release formu-lation, terfenadine 60 mg, or placebo.Study drugs were blinded, using a dou-ble-dummy technique. Study medica-tions were taken twice daily for 14days. Subjects agreed not to use othertreatments for allergic rhinitis or med-ications, alcohol, and other drugsknown to alter consciousness or mentalstatus. Maintenance desensitizationtherapy was permitted and those withasthma were allowed to continue to useoral sympathomimetic medications, ifneeded.

Subjects returned to the site on treat-ment days 3, 7, and 14. At each visit,the physician repeated the symptomseverity ratings and the investigatorand the subject separately rated theoverall effectiveness of treatment on ascale from 0 � poor to 10 � excellent.Subjects were also interviewed regard-ing the occurrence of any adverse ex-periences.

Statistical MethodsStatistical analyses were performed onthe pooled data from the three investi-gational sites. Baseline treatmentgroup comparability was evaluated us-ing the Cochran-Mantel-Haenszel test,controlling for site, for categoricalvariables (eg, sex, race, medical back-ground) and the two-way analysis ofvariance (ANOVA), with effects fortreatment, site, and treatment-by-siteinteraction, for variables with continu-ous distribution (eg, age, weight). In-dividual symptom scores weresummed to create a total symptomscore for each treatment group for eachvisit. As a separate group, the individ-ual symptom scores for the nasal-re-lated allergy symptoms of rhinorrhea,sneezing, and nasal blockage were alsosummed to create total symptomscores for each group for each visit.Mean scores were calculated for thephysician and subject global assess-ments. For each of these variables,overall comparability of the treatmentgroups and pairwise comparisons wereanalyzed using the Cochran-Mantel-Haenszel test, controlling for site, us-ing modified ridit scores. Adverseevent frequencies were compared us-ing Fischer’s Exact test. Statistical sig-nificance was declared if the probabil-ity of an observed difference being dueto random occurrence was �.05.

RESULTSStudy PopulationA total of 287 eligible subjects wereenrolled. The average age of the studypopulation was 39 years (range: 15 to81 years); 196 were women and 91

were men. The majority of subjects(61.6%) had histories of both seasonaland perennial rhinitis. In 89% of sub-jects, the nasal mucosa was red andswollen; 10.8% of subjects had com-plete nasal obstruction. Randomizationresulted in the following group sizes:96 received brompheniramine, 96 re-ceived terfenadine, and 95 receivedplacebo. Demographic and baselinecharacteristics were similar amongtreatment groups (Table 1).Fifty-seven subjects did not com-

plete the full study period: 32 failed toattend scheduled visits or were unableto comply with the study protocol, 18had adverse events that precipitatedwithdrawal from the study; and 7 hadintercurrent illnesses. Data from 27 ofthese 57 subjects, however, were suf-ficient to be included in the efficacyanalyses. As a result, there were 257subjects analyzed for efficacy: 82 re-ceived brompheniramine, 87 receivedterfenadine, and 88 received placebo.Data from all 287 subjects were in-cluded in the analysis for safety.

Symptom SeverityFigure 1 shows the summed severityscores for all symptoms of allergic rhi-nitis (ie, rhinorrhea; sneezing; nasalblockage; pruritus of the eyes, nose orpharynx; excessive lacrimation; andpostnasal drip). The three treatmentgroups were comparable at baseline.Beginning at day 3 and continuingthrough days 7 and 14, symptom im-provement (ie, a decrease in thesummed symptom score) was signifi-cantly greater in the brompheniramine-treatment group, compared with boththe terfenadine-treatment and placebo-treatment groups. The decrease inmean summed symptom score amongterfenadine-treated subjects was con-sistently greater than in placebo-treated subjects, however, this differ-ence did not achieve statisticalsignificance. The mean individualsymptom scores generally paralleledthe pattern seen for the summed symp-tom scores in the three groups (ie, thelargest decrease was seen amongbrompheniramine-treated subjects com-

366 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

pared with both terfenadine-treatedsubjects or those taking placebo).The summed scores for the nasal

symptoms cluster (ie, rhinorrhea,sneezing, blockage) are presented inTable 2. Improvement in these nasalsymptoms was significantly greater inthe brompheniramine-treated subjectsthan in the terfenadine-treated and pla-cebo-treated subjects at 3, 7, and 14days. Similar to the results seen withthe summed score for all symptoms,the improvement in nasal symptoms inthe terfenadine-treatment group wasgreater than in the placebo group, how-ever, this difference did not reach sta-tistical significance.

Overall TreatmentThe results of the physician’s assess-ment of overall treatment efficacy (Ta-ble 3) demonstrated that bromphenira-mine had significantly better ratings atdays 3, 7, and 14 than terfenadine andplacebo. The results for terfenadinewere significantly better than placeboat day 14. The subject’s assessment ofoverall treatment efficacy at days 3, 7,and 14 demonstrated that bromphe-niramine-treated subjects rated theirmedication as significantly more effec-tive than did those receiving either ter-fenadine or placebo (Table 4); on day

14, the difference between terfenadine-treated and placebo-treated subjectsapproached statistical significance(P � .07).

SafetyOne or more adverse experiences werereported by 166 (57.8%) of the 287subjects who received study medica-

tion (Table 5). A significantly greater(P � .05) number of bromphenira-mine-treated subjects (70.8%) reportedadverse events, compared with terfena-dine-treated subjects (53.1%) and pla-cebo-treated subjects (49.5%). Symp-toms related to the central nervoussystem or to the body as a whole werethe most frequently reported in alltreatment groups. Somnolence andheadache were the most common spe-cific adverse events. Somnolence wasreported significantly more frequentlyamong brompheniramine-treated sub-jects (41.7%) compared with terfena-dine-treated subjects (9.4%) or to thosereceiving placebo (10.5%). Reports ofsomnolence tended to be less frequentas treatment continued (Table 6).Headache was reported significantlymore frequently among terfenadine-treated subjects (28.1%) comparedwith brompheniramine-treated sub-jects (14.6%).Eighteen subjects withdrew from the

study due to adverse experiences. Asignificantly (P � .05) greater numberof brompheniramine-treated subjects(12) withdrew due to adverse experi-ences, compared with terfenadine-treated subjects (3) and placebo-treatedsubjects (3). The most frequent ad-

Figure 1. Summed symptom score over time for allergic rhinitis patients treated with extended-releasebrompheniramine 12 mg bid (N� 82), terfenadine 60 mg bid (N� 87), and placebo (N� 88). Summedscore includes individual ratings for rhinorrhea; sneezing; ocular pruritus; nasal pruritus; pharyngealpruritus; excessive lacrimation; and postnasal drip. **P� .01 vs placebo. ***P� .001 vs placebo.�P�

.05 vs terfenadine.

Table 1. Baseline Characteristics

BrompheniramineMaleate, 12 mg

(N � 96)

Terfenadine, 60 mg(N � 96)

Placebo(N � 95)

Male/females 31 /65 27 /69 33 /62Mean Age, yr 39.6 39.4 37.9

Range 16–79 15–74 15–81Mean height, cm 167.4 168.4 169.2

Range 142.2–193.0 152.4–188.0 144.8–188.0Mean weight, kg 70.9 74.5 75.9

Range 43.6–109.1 39.5–143.2 47.3–141.8Current rhinitis type

Seasonal (hay fever) 21 (21.9%) 18 (18.8%) 23 (24.2%)Perennial 12 (12.5%) 19 (19.8%) 17 (17.9%)Both 63 (65.6%) 59 (61.5%) 55 (57.9%)

Nasal mucosaNormal 0 0 0Slightly swollen, red 34 (35.4%) 32 (33.3%) 35 (36.8%)Very swollen 47 (49.0%) 56 (58.3%) 52 (54.7%)Total obstruction 15 (15.6%) 8 (8.3%) 8 (8.4%)


verse experience necessitating with-drawal from the study prematurely wassomnolence in brompheniramine-treated subjects and headache amongsubjects taking terfenadine.

DISCUSSIONAntihistamines are widely accepted aseffective in the management of symp-toms of allergic rhinitis and numerousagents are available both by prescrip-tion and over the counter. The newersecond-generation H1 antagonists areconsidered to have an improved risk-benefit ratio compared with their pre-decessors. Nevertheless, many of thefirst-generation medications are highlyeffective and may offer greater advan-tage to the patient.To our knowledge, this trial is the

first reported comparison of non-prescription brompheniramine, in anextended-release formulation, andterfenadine, a second-generation pre-

scription antihistamine. The purpose ofthe study was to compare the effects oftreatment in subjects with moderate tosevere symptoms of allergic rhinitis,utilizing the recommended adult doses(ie, brompheniramine 12 mg twice aday and terfenadine 60 mg twice aday).All subjects entered the current

study with moderate to severe symp-

toms and by day 3 of treatment brom-pheniramine-treated subjects showedsignificant improvement in symptomseverity compared with those inthe terfenadine-treatment or placebo-treatment groups. Compared withterfenadine-treated subjects, brom-pheniramine-treated subjects contin-ued to show significant improvementthroughout the 14-day study period.The effectiveness of brompheniraminewas also evident in the results of theglobal evaluations. Both physiciansand subjects considered bromphenira-mine to be significantly more effectivethan terfenadine.This study demonstrates that a

classic alkylamine antihistamine, suchas brompheniramine, can providesignificant relief of allergic rhinitissymptoms. Furthermore, these resultsdemonstrate that nonprescription, ex-tended-release brompheniramine pro-vides greater relief compared with pre-scription terfenadine. Further, theseresults are consistent with those ofother clinical trials where terfenadinehas been reported to be superior toplacebo, but not significantly more ef-fective than other first-generation anti-histamines.13–16First-generation antihistamines are

historically associated with sedativeeffects. Not surprisingly, in this trial,subjects taking brompheniramine re-ported sedation significantly more fre-quently than terfenadine-treated sub-jects. Of note, however, the frequencyof somnolence reports lessened overtime. Headache occurred significantly

Table 2. Nasal symptoms cluster* summed severity scores (mean � SD)


(N � 82)

Terfenadine,60 mg

(N � 87)

Placebo(N � 88)

Baseline 6.6 � 2.6 6.2 � 2.4 6.2 � 2.3Day 3 3.1 � 2.2†‡ 4.0 � 2.7 4.5 � 2.8Day 7 2.8 � 2.1†� 3.9 � 2.8 4.0 � 2.6Day 14 2.4 � 2.1§� 3.6 � 2.8 3.9 � 2.9

* Rhinorrhea, sneezing, nasal blockage.† P � .01 vs placebo.‡ P � .05 vs terfenadine.§ P � .001 vs placebo.� P � .01 vs terfenadine.

Table 3. Physician’s Global Evaluation* (mean � SD)


(N � 81)


Placebo(N � 88)

Day 3 6.4 � 2.5†§ 4.7 � 3.0 4.6 � 3.1Day 7 6.9 � 2.4‡§ 5.5 � 2.9 5.4 � 3.3Day 14 7.7 � 2.0†§ 6.3 � 2.8� 5.4 � 3.4

* Scale: 0 � poor to 10 � excellent.† P � .001 vs placebo.‡ P � .01 vs placebo.§ P � .01 vs terfenadine.� P � .05 vs placebo.

Table 4. Subjects’ Global Evaluation* (mean � SD)


(N � 81)


Placebo(N � 88)

Day 3 6.0 � 2.6†‡ 4.8 � 2.9 4.1 � 3.0Day 7 6.5 � 2.5§‡ 5.2 � 3.0 5.0 � 3.1Day 14 7.4 � 2.2†‡ 5.7 � 3.1� 4.9 � 3.3

* Scale: 0 � poor to 10 � excellent.† P � .001 vs placebo.‡ P � .01 vs terfenadine.§ P � .01 vs placebo.� P � .07 vs placebo.


more frequently among the terfena-dine-treated subjects compared withbrompheniramine-treated subjects.This increased frequency of headacheassociated with terfenadine has alsobeen reported in other comparativeclinical trials13,15 as well as in terfena-dine prescribing information.17Efficacy and side-effect profiles

play important roles in how physiciansand their patients choose an antihista-mine. In an era of increasingly con-strained healthcare resources, consid-eration of relative cost may also guidethe selection of optimal allergic rhinitistreatment. By way of example, the 14-day study regimen, based on the aver-age 1995 wholesale cost, wouldamount to $6.83 for brompheniramine(12 mg bid); the corresponding cost forterfenadine (60 mg bid) is $25.76.18This study’s data confirm the well-

known finding from controlled clinicaltrials that first-generation antihista-mines are associated with an increased

frequency of sedation compared withplacebo or a nonsedating antihista-mine. The data also point out a fre-quently overlooked corollary—manypeople can tolerate a first-generationantihistamine without sedation. Non-prescription antihistamine class label-ing contains warnings against use ofthese products in situations where therisk of a sedative potential with a first-generation antihistamine like brom-pheniramine may outweigh any corre-sponding benefit. The occurrence ofsomnolence or performance impair-ment in an individual patient shouldsuggest that an alternative agent couldbe a more appropriate clinical choicefor that individual. Nonetheless, the re-sults of this study demonstrate thatsymptom relief can be obtained fromextended-release brompheniraminewithout the attendant costs of prescrib-ing or dispensing a prescription anti-histamine.

ACKNOWLEDGMENTSWe thank Howard Hassman, DO, ofFamily Practice Associates, San Di-ego, CA, for his participation in thisstudy.We thank Mr. Lawrence Marinucci

from Whitehall-Robins, Madison, NJ,for providing statistical analyses andMs. Barbara Stern for assistance in thepreparation of this manuscript.

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Table 5. Adverse Events


(N � 96)


Placebo(N � 95)

Body as a whole 17 28 23Gastrointestinal 7 7 6Nervous*† 56 20 21Skin 2 1 1Respiratory 5 7 5Cardiovascular 0 3 1Genitourinary 1 0 2Special Senses 3 3 0Musculoskeletal 0 0 1Subjects reporting

any event‡68 51 47

* P � .01 among treatment groups.† See Table 6.‡P � .05 among treatment groups.

Table 6. Proportion of Subjects Reporting Somnolence


Terfenadine, 60 mg Placebo

Day 3 40% 10% 10%Day 7 27% 7% 9%Day 14 24% 4% 5%


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Address correspondence to:Sandy A. Furey, PhD, MD.Whitehall Robins HealthcareFive Giralda FarmsMadison, NJ 07940


brompheniramine, terfenadine, and placebo in allergic rhinitis

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