- Email: [email protected]
Brompheniramine, Terfenadine, and Placebo in Allergic Rhinitis
Brompheniramine, terfenadine, and placebo in allergic rhinitis Gerald L Klein, MD*; Thomas Littlejohn, III, MD**; Earle A Lockhart, MD†; and Sandy A Furey, PhD, MD†
Background: Second-generation antihistamines, reported to lack central nervous system depressant activity, may be considered to have a clinical advantage over traditional antihistamines. Objective: To compare the effectiveness, at recommended doses, of an extendedrelease formulation of nonprescription brompheniramine and prescription terfenadine 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 brompheniramine 12 mg (n ⫽ 96), terfenadine 60 mg (n ⫽ 96), or placebo (n ⫽ 95) twice daily for 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, the investigator assessed symptom severity (ie, rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). The investigator and the subject each completed a global efficacy evaluation, and subjects were interviewed regarding the occurrence of adverse experiences. Symptoms were analyzed as summed severity scores for (1) all symptoms and (2) for the symptom cluster of rhinorrhea, sneezing, and nasal blockage. Results: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P ⱕ .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. Terfenadine was significantly better (P ⱕ .05) than placebo on the physician’s global at day 14. Central nervous system-related complaints were the most frequently reported adverse experiences among all three groups; somnolence was reported most frequently by brompheniramine-treated subjects. Conclusion: A nonprescription, extended-release formulation of brompheniramine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitis than terfenadine, 60 mg bid. Ann Allergy Asthma Immunol 1996;77:365–70.
INTRODUCTION Allergic rhinitis is the most common reaction to antigen stimulation involving histamine release. Up to 22% of the US population is affected by a variety of plant and tree pollen on a seasonal basis, while a lesser percentage suffers throughout the year because of
Presented in part at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Ninety-Sixth Annual Meeting, San Diego, 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
house dust, molds, and animal dander.1–3 Allergic rhinitis manifests itself as a complex of symptoms that can include itching, sneezing, tearing, and nasal discharge. For decades, antihistamines have been the mainstay of treatment; many are available without a prescription. More recently, the use of “second-generation” H1-receptor antagonists has grown rapidly. Unlike the first-generation antihistamines, which can sometimes be associated with central nervous system effects,4 –5 the newer H1 antagonists are reported to be largely devoid of central nervous system depressant activity and, thus, may be considered to have a clinical advantage.6 – 8
Brompheniramine, a classic antihistamine, has been available for more than 30 years as a nonprescription medication for the relief of the symptoms of allergic rhinitis. The effectiveness of brompheniramine has been demonstrated in clinical trials and, in comparative studies, was found to have a lower frequency of adverse effects than other conventional antihistamines.9 –12 Terfenadine, the first nonsedating antihistamine approved for use in the United States, has also been shown in clinical trials to be effective in providing symptom relief and it is reported to have a frequency of sedation comparable to placebo.13–15 To our knowledge, these two medications have not been previously compared in a randomized, double-blind, placebo-controlled trial. The purpose of this study was to evaluate the effects of treatment with standard recommended doses of an extended-release formulation of nonprescription brompheniramine and prescription terfenadine in subjects with symptoms of allergic rhinitis.
MATERIALS AND METHODS Subjects The study population comprised adult men and women, 15 years of age or over, with a history of allergic rhinitis. All presented with symptoms, had corroborating evidence of nasal mucosal changes consistent with exposure to an antigen (ie, pallor, injection, edema), and positive skin tests to at least one allergen. Those who had taken astemizole within 30 days of the study, allergy medication within 72 hours, or an antihistamine within 24 hours were not eligible. Women who were pregnant, nursing, or at risk for pregnancy
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were also not eligible. Other reasons for exclusion were any medical condition or use of any treatment that would interfere with the interpretation of study results, or contraindication to antihistamine use. Procedures This was a double-blind, placebo-controlled, parallel-group, multicenter study. The study was conducted at two sites in California and one in North Carolina; subjects participated on an outpatient basis. The study protocol received Institutional Review Board Approval. All subjects, and a parent or guardian where appropriate, signed an informed consent document prior to treatment. At the first visit, subjects provided medical and allergy histories and underwent brief physical examinations, with particular emphasis on the eyes, nose, and throat to confirm the presence of allergic rhinitis. The physician evaluated the subject for the specific symptoms of rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose,1 or pharynx; excessive lacrimation; and postnasal drip. The severity of each symptom was rated on a 5-point scale as follows: 0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, 3 ⫽ severe, 4 ⫽ very severe. To qualify for randomization, two or more of the symptoms had to be at least moderate in severity (a score of 2 or higher) and at least one of these two symptoms had to include rhinorrhea, sneezing, nasal blockage, or postnasal drip. Subjects received brompheniramine (12 mg) in an extended-release formulation, terfenadine 60 mg, or placebo. Study drugs were blinded, using a double-dummy technique. Study medications were taken twice daily for 14 days. Subjects agreed not to use other treatments for allergic rhinitis or medications, alcohol, and other drugs known to alter consciousness or mental status. Maintenance desensitization therapy was permitted and those with asthma were allowed to continue to use oral sympathomimetic medications, if needed.
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Subjects returned to the site on treatment days 3, 7, and 14. At each visit, the physician repeated the symptom severity ratings and the investigator and the subject separately rated the overall effectiveness of treatment on a scale from 0 ⫽ poor to 10 ⫽ excellent. Subjects were also interviewed regarding the occurrence of any adverse experiences. Statistical Methods Statistical analyses were performed on the pooled data from the three investigational sites. Baseline treatment group comparability was evaluated using the Cochran-Mantel-Haenszel test, controlling for site, for categorical variables (eg, sex, race, medical background) and the two-way analysis of variance (ANOVA), with effects for treatment, site, and treatment-by-site interaction, for variables with continuous distribution (eg, age, weight). Individual symptom scores were summed to create a total symptom score for each treatment group for each visit. As a separate group, the individual symptom scores for the nasal-related allergy symptoms of rhinorrhea, sneezing, and nasal blockage were also summed to create total symptom scores for each group for each visit. Mean scores were calculated for the physician and subject global assessments. For each of these variables, overall comparability of the treatment groups and pairwise comparisons were analyzed using the Cochran-MantelHaenszel test, controlling for site, using modified ridit scores. Adverse event frequencies were compared using Fischer’s Exact test. Statistical significance was declared if the probability of an observed difference being due to random occurrence was ⱕ.05.
RESULTS Study Population A total of 287 eligible subjects were enrolled. The average age of the study population was 39 years (range: 15 to 81 years); 196 were women and 91
were men. The majority of subjects (61.6%) had histories of both seasonal and perennial rhinitis. In 89% of subjects, the nasal mucosa was red and swollen; 10.8% of subjects had complete nasal obstruction. Randomization resulted in the following group sizes: 96 received brompheniramine, 96 received terfenadine, and 95 received placebo. Demographic and baseline characteristics were similar among treatment groups (Table 1). Fifty-seven subjects did not complete the full study period: 32 failed to attend scheduled visits or were unable to comply with the study protocol, 18 had adverse events that precipitated withdrawal from the study; and 7 had intercurrent illnesses. Data from 27 of these 57 subjects, however, were sufficient to be included in the efficacy analyses. As a result, there were 257 subjects analyzed for efficacy: 82 received brompheniramine, 87 received terfenadine, and 88 received placebo. Data from all 287 subjects were included in the analysis for safety. Symptom Severity Figure 1 shows the summed severity scores for all symptoms of allergic rhinitis (ie, rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose or pharynx; excessive lacrimation; and postnasal drip). The three treatment groups were comparable at baseline. Beginning at day 3 and continuing through days 7 and 14, symptom improvement (ie, a decrease in the summed symptom score) was significantly greater in the brompheniraminetreatment group, compared with both the terfenadine-treatment and placebotreatment groups. The decrease in mean summed symptom score among terfenadine-treated subjects was consistently greater than in placebotreated subjects, however, this difference did not achieve statistical significance. The mean individual symptom scores generally paralleled the pattern seen for the summed symptom scores in the three groups (ie, the largest decrease was seen among brompheniramine-treated subjects com-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 1. Baseline Characteristics Brompheniramine Maleate, 12 mg (N ⴝ 96)
Terfenadine, 60 mg (N ⴝ 96)
Placebo (N ⴝ 95)
31 /65 39.6 16–79 167.4 142.2–193.0 70.9 43.6–109.1
27 /69 39.4 15–74 168.4 152.4–188.0 74.5 39.5–143.2
33 /62 37.9 15–81 169.2 144.8–188.0 75.9 47.3–141.8
21 (21.9%) 12 (12.5%) 63 (65.6%)
18 (18.8%) 19 (19.8%) 59 (61.5%)
23 (24.2%) 17 (17.9%) 55 (57.9%)
0 34 (35.4%) 47 (49.0%) 15 (15.6%)
0 32 (33.3%) 56 (58.3%) 8 (8.3%)
0 35 (36.8%) 52 (54.7%) 8 (8.4%)
Male/females Mean Age, yr Range Mean height, cm Range Mean weight, kg Range Current rhinitis type Seasonal (hay fever) Perennial Both Nasal mucosa Normal Slightly swollen, red Very swollen Total obstruction
pared with both terfenadine-treated subjects or those taking placebo). The summed scores for the nasal symptoms cluster (ie, rhinorrhea, sneezing, blockage) are presented in Table 2. Improvement in these nasal symptoms was significantly greater in the brompheniramine-treated subjects than in the terfenadine-treated and placebo-treated subjects at 3, 7, and 14 days. Similar to the results seen with the summed score for all symptoms, the improvement in nasal symptoms in the terfenadine-treatment group was greater than in the placebo group, however, this difference did not reach statistical significance. Overall Treatment The results of the physician’s assessment of overall treatment efficacy (Table 3) demonstrated that brompheniramine had significantly better ratings at days 3, 7, and 14 than terfenadine and placebo. The results for terfenadine were significantly better than placebo at day 14. The subject’s assessment of overall treatment efficacy at days 3, 7, and 14 demonstrated that brompheniramine-treated subjects rated their medication as significantly more effective than did those receiving either terfenadine or placebo (Table 4); on day
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14, the difference between terfenadinetreated and placebo-treated subjects approached statistical significance (P ⫽ .07). Safety One or more adverse experiences were reported by 166 (57.8%) of the 287 subjects who received study medica-
tion (Table 5). A significantly greater (P ⱕ .05) number of brompheniramine-treated subjects (70.8%) reported adverse events, compared with terfenadine-treated subjects (53.1%) and placebo-treated subjects (49.5%). Symptoms related to the central nervous system or to the body as a whole were the most frequently reported in all treatment groups. Somnolence and headache were the most common specific adverse events. Somnolence was reported significantly more frequently among brompheniramine-treated subjects (41.7%) compared with terfenadine-treated subjects (9.4%) or to those receiving placebo (10.5%). Reports of somnolence tended to be less frequent as treatment continued (Table 6). Headache was reported significantly more frequently among terfenadinetreated subjects (28.1%) compared with brompheniramine-treated subjects (14.6%). Eighteen subjects withdrew from the study due to adverse experiences. A significantly (P ⱕ .05) greater number of brompheniramine-treated subjects (12) withdrew due to adverse experiences, compared with terfenadinetreated subjects (3) and placebo-treated subjects (3). The most frequent ad-
Figure 1. Summed symptom score over time for allergic rhinitis patients treated with extended-release brompheniramine 12 mg bid (N ⫽ 82), terfenadine 60 mg bid (N ⫽ 87), and placebo (N ⫽ 88). Summed score includes individual ratings for rhinorrhea; sneezing; ocular pruritus; nasal pruritus; pharyngeal pruritus; excessive lacrimation; and postnasal drip. **P ⱕ .01 vs placebo. ***P ⱕ .001 vs placebo. ⫹P ⱕ .05 vs terfenadine.
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Table 2. Nasal symptoms cluster* summed severity scores (mean ⫾ SD)
Baseline Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 82)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.6 ⫾ 2.6 3.1 ⫾ 2.2†‡ 2.8 ⫾ 2.1†㛳 2.4 ⫾ 2.1§㛳
6.2 ⫾ 2.4 4.0 ⫾ 2.7 3.9 ⫾ 2.8 3.6 ⫾ 2.8
6.2 ⫾ 2.3 4.5 ⫾ 2.8 4.0 ⫾ 2.6 3.9 ⫾ 2.9
* Rhinorrhea, sneezing, nasal blockage. † P ⱕ .01 vs placebo. ‡ P ⱕ .05 vs terfenadine. § P ⱕ .001 vs placebo. 㛳 P ⱕ .01 vs terfenadine. Table 3. Physician’s Global Evaluation* (mean ⫾ SD)
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 81)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.4 ⫾ 2.5†§ 6.9 ⫾ 2.4‡§ 7.7 ⫾ 2.0†§
4.7 ⫾ 3.0 5.5 ⫾ 2.9 6.3 ⫾ 2.8㛳
4.6 ⫾ 3.1 5.4 ⫾ 3.3 5.4 ⫾ 3.4
* Scale: 0 ⫽ poor to 10 ⫽ excellent. † P ⱕ .001 vs placebo. ‡ P ⱕ .01 vs placebo. § P ⱕ .01 vs terfenadine. 㛳 P ⱕ .05 vs placebo.
verse experience necessitating withdrawal from the study prematurely was somnolence in brompheniraminetreated subjects and headache among subjects taking terfenadine. DISCUSSION Antihistamines are widely accepted as effective in the management of symptoms of allergic rhinitis and numerous agents are available both by prescription and over the counter. The newer second-generation H1 antagonists are considered to have an improved riskbenefit ratio compared with their predecessors. Nevertheless, many of the first-generation medications are highly effective and may offer greater advantage to the patient. To our knowledge, this trial is the first reported comparison of nonprescription brompheniramine, in an extended-release formulation, and terfenadine, a second-generation pre-
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scription antihistamine. The purpose of the study was to compare the effects of treatment in subjects with moderate to severe symptoms of allergic rhinitis, utilizing the recommended adult doses (ie, brompheniramine 12 mg twice a day and terfenadine 60 mg twice a day). All subjects entered the current study with moderate to severe symp-
toms and by day 3 of treatment brompheniramine-treated subjects showed significant improvement in symptom severity compared with those in the terfenadine-treatment or placebotreatment groups. Compared with terfenadine-treated subjects, brompheniramine-treated subjects continued to show significant improvement throughout the 14-day study period. The effectiveness of brompheniramine was also evident in the results of the global evaluations. Both physicians and subjects considered brompheniramine to be significantly more effective than terfenadine. This study demonstrates that a classic alkylamine antihistamine, such as brompheniramine, can provide significant relief of allergic rhinitis symptoms. Furthermore, these results demonstrate that nonprescription, extended-release brompheniramine provides greater relief compared with prescription terfenadine. Further, these results are consistent with those of other clinical trials where terfenadine has been reported to be superior to placebo, but not significantly more effective than other first-generation antihistamines.13–16 First-generation antihistamines are historically associated with sedative effects. Not surprisingly, in this trial, subjects taking brompheniramine reported sedation significantly more frequently than terfenadine-treated subjects. Of note, however, the frequency of somnolence reports lessened over time. Headache occurred significantly
Table 4. Subjects’ Global Evaluation* (mean ⫾ SD)
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 81)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.0 ⫾ 2.6†‡ 6.5 ⫾ 2.5§‡ 7.4 ⫾ 2.2†‡
4.8 ⫾ 2.9 5.2 ⫾ 3.0 5.7 ⫾ 3.1㛳
4.1 ⫾ 3.0 5.0 ⫾ 3.1 4.9 ⫾ 3.3
* Scale: 0 ⫽ poor to 10 ⫽ excellent. † P ⱕ .001 vs placebo. ‡ P ⱕ .01 vs terfenadine. § P ⱕ .01 vs placebo. 㛳 P ⫽ .07 vs placebo.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 5. Adverse Events Brompheniramine Maleate, 12 mg (N ⴝ 96)
Terfenadine, 60 mg (N ⴝ 96)
Placebo (N ⴝ 95)
17 7 56 2 5 0 1 3 0 68
28 7 20 1 7 3 0 3 0 51
23 6 21 1 5 1 2 0 1 47
Body as a whole Gastrointestinal Nervous*† Skin Respiratory Cardiovascular Genitourinary Special Senses Musculoskeletal Subjects reporting any event‡ * P ⬍ .01 among treatment groups. † See Table 6. ‡P ⬍ .05 among treatment groups.
Table 6. Proportion of Subjects Reporting Somnolence
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg
Terfenadine, 60 mg
Placebo
40% 27% 24%
10% 7% 4%
10% 9% 5%
more frequently among the terfenadine-treated subjects compared with brompheniramine-treated subjects. This increased frequency of headache associated with terfenadine has also been reported in other comparative clinical trials13,15 as well as in terfenadine prescribing information.17 Efficacy and side-effect profiles play important roles in how physicians and their patients choose an antihistamine. In an era of increasingly constrained healthcare resources, consideration of relative cost may also guide the selection of optimal allergic rhinitis treatment. By way of example, the 14day study regimen, based on the average 1995 wholesale cost, would amount to $6.83 for brompheniramine (12 mg bid); the corresponding cost for terfenadine (60 mg bid) is $25.76.18 This study’s data confirm the wellknown finding from controlled clinical trials that first-generation antihistamines are associated with an increased
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frequency of sedation compared with placebo or a nonsedating antihistamine. The data also point out a frequently overlooked corollary—many people can tolerate a first-generation antihistamine without sedation. Nonprescription antihistamine class labeling contains warnings against use of these products in situations where the risk of a sedative potential with a firstgeneration antihistamine like brompheniramine may outweigh any corresponding benefit. The occurrence of somnolence or performance impairment in an individual patient should suggest that an alternative agent could be a more appropriate clinical choice for that individual. Nonetheless, the results of this study demonstrate that symptom relief can be obtained from extended-release brompheniramine without the attendant costs of prescribing or dispensing a prescription antihistamine.
ACKNOWLEDGMENTS We thank Howard Hassman, DO, of Family Practice Associates, San Diego, CA, for his participation in this study. We thank Mr. Lawrence Marinucci from Whitehall-Robins, Madison, NJ, for providing statistical analyses and Ms. Barbara Stern for assistance in the preparation of this manuscript. REFERENCES 1. Naclerio RM. Allergic rhinitis. N Engl J Med 1991;325:860 –9. 2. Kaliner MA. Allergic rhinitis. In: Mygind N, Naclerio RM, eds. Allergic and non-allergic rhinitis. Clinical aspects. Philadelphia: W B Saunders, 1993:153– 8. 3. Badhwar AK, Druce HM. Allergic rhinitis. Med Clin N Am 1992;76: 789 – 803. 4. Simons FER. H1-receptor antagonists. Comparative tolerability and safety. Drug Safety 1994;10:350 – 80. 5. Meltzer EO. Comparative safety of H1 antihistamines. Ann Allergy 1991;67: 625–33. 6. Simons FER, Simons KJ. Secondgeneration H1-receptor antagonists. Ann Allergy 1991;66:6 –19. 7. Drouin MA. H1 antihistamines: Perspective on the use of the conventional and new agents. Ann Allergy 1985;55: 747–52. 8. Kaliner MA, Check WA. Non-sedating antihistamines. Allergy Proc 1988; 9:649 – 61. 9. Lipman WH. The clinical evaluation of parabromdylamine maleate. Ann Allergy 1959;17:19 –24. 10. Schiller IW, Lowell FG. Further use of color coding in drug evaluations; parabromdylamine in perennial allergic rhinitis. N Engl J Med 1959;261: 478 – 82. 11. Grater WC. Comparative effectiveness of two antihistamines in allergic rhinitis. Arch Otolaryngol 1960;72:63–5. 12. MacLaren WR. Parabromdylamine maleate, chlorprophenpyridine maleate and tripelennamine hydrochloride in chronic allergic rhinitis. J Allergy 1959;30:235– 40. 13. Kemp JP, Buckley CE, Gershwin ME, et al. Multicenter double-blind, placebo-controlled trial of terfenadine in seasonal allergic rhinitis and conjunctivitis. Ann Allergy 1985;54:502–9.
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14. Buckley CE, Buchman E, Falliers CJ, et al. Terfenadine treatment of fall hay fever. Ann Allergy 1988;60:123– 8. 15. McTavish D, Goa KL, Ferrill M. Terfenadine. An updated review of its pharmacological properties and therapeutic efficacy. Drugs 1990;39: 552–74.
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16. Brostoff J, Lockhart JDF. Controlled trial of terfenadine and chlorpheniramine maleate in perennial rhinitis. Postgrad Med J 1982;58:422–3. 17. Physicians’ Desk Reference. Montvale, NJ: Medical Economics 1995:1430. 18. 1995 Drug Topics Red Book.
Montvale, NJ: Medical Economics 1995;409,540. Address correspondence to: Sandy A. Furey, PhD, MD. Whitehall Robins Healthcare Five Giralda Farms Madison, NJ 07940
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Background: Second-generation antihistamines, reported to lack central nervous system depressant activity, may be considered to have a clinical advantage over traditional antihistamines. Objective: To compare the effectiveness, at recommended doses, of an extendedrelease formulation of nonprescription brompheniramine and prescription terfenadine 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 brompheniramine 12 mg (n ⫽ 96), terfenadine 60 mg (n ⫽ 96), or placebo (n ⫽ 95) twice daily for 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, the investigator assessed symptom severity (ie, rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). The investigator and the subject each completed a global efficacy evaluation, and subjects were interviewed regarding the occurrence of adverse experiences. Symptoms were analyzed as summed severity scores for (1) all symptoms and (2) for the symptom cluster of rhinorrhea, sneezing, and nasal blockage. Results: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P ⱕ .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. Terfenadine was significantly better (P ⱕ .05) than placebo on the physician’s global at day 14. Central nervous system-related complaints were the most frequently reported adverse experiences among all three groups; somnolence was reported most frequently by brompheniramine-treated subjects. Conclusion: A nonprescription, extended-release formulation of brompheniramine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitis than terfenadine, 60 mg bid. Ann Allergy Asthma Immunol 1996;77:365–70.
INTRODUCTION Allergic rhinitis is the most common reaction to antigen stimulation involving histamine release. Up to 22% of the US population is affected by a variety of plant and tree pollen on a seasonal basis, while a lesser percentage suffers throughout the year because of
Presented in part at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Ninety-Sixth Annual Meeting, San Diego, 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
house dust, molds, and animal dander.1–3 Allergic rhinitis manifests itself as a complex of symptoms that can include itching, sneezing, tearing, and nasal discharge. For decades, antihistamines have been the mainstay of treatment; many are available without a prescription. More recently, the use of “second-generation” H1-receptor antagonists has grown rapidly. Unlike the first-generation antihistamines, which can sometimes be associated with central nervous system effects,4 –5 the newer H1 antagonists are reported to be largely devoid of central nervous system depressant activity and, thus, may be considered to have a clinical advantage.6 – 8
Brompheniramine, a classic antihistamine, has been available for more than 30 years as a nonprescription medication for the relief of the symptoms of allergic rhinitis. The effectiveness of brompheniramine has been demonstrated in clinical trials and, in comparative studies, was found to have a lower frequency of adverse effects than other conventional antihistamines.9 –12 Terfenadine, the first nonsedating antihistamine approved for use in the United States, has also been shown in clinical trials to be effective in providing symptom relief and it is reported to have a frequency of sedation comparable to placebo.13–15 To our knowledge, these two medications have not been previously compared in a randomized, double-blind, placebo-controlled trial. The purpose of this study was to evaluate the effects of treatment with standard recommended doses of an extended-release formulation of nonprescription brompheniramine and prescription terfenadine in subjects with symptoms of allergic rhinitis.
MATERIALS AND METHODS Subjects The study population comprised adult men and women, 15 years of age or over, with a history of allergic rhinitis. All presented with symptoms, had corroborating evidence of nasal mucosal changes consistent with exposure to an antigen (ie, pallor, injection, edema), and positive skin tests to at least one allergen. Those who had taken astemizole within 30 days of the study, allergy medication within 72 hours, or an antihistamine within 24 hours were not eligible. Women who were pregnant, nursing, or at risk for pregnancy
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were also not eligible. Other reasons for exclusion were any medical condition or use of any treatment that would interfere with the interpretation of study results, or contraindication to antihistamine use. Procedures This was a double-blind, placebo-controlled, parallel-group, multicenter study. The study was conducted at two sites in California and one in North Carolina; subjects participated on an outpatient basis. The study protocol received Institutional Review Board Approval. All subjects, and a parent or guardian where appropriate, signed an informed consent document prior to treatment. At the first visit, subjects provided medical and allergy histories and underwent brief physical examinations, with particular emphasis on the eyes, nose, and throat to confirm the presence of allergic rhinitis. The physician evaluated the subject for the specific symptoms of rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose,1 or pharynx; excessive lacrimation; and postnasal drip. The severity of each symptom was rated on a 5-point scale as follows: 0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, 3 ⫽ severe, 4 ⫽ very severe. To qualify for randomization, two or more of the symptoms had to be at least moderate in severity (a score of 2 or higher) and at least one of these two symptoms had to include rhinorrhea, sneezing, nasal blockage, or postnasal drip. Subjects received brompheniramine (12 mg) in an extended-release formulation, terfenadine 60 mg, or placebo. Study drugs were blinded, using a double-dummy technique. Study medications were taken twice daily for 14 days. Subjects agreed not to use other treatments for allergic rhinitis or medications, alcohol, and other drugs known to alter consciousness or mental status. Maintenance desensitization therapy was permitted and those with asthma were allowed to continue to use oral sympathomimetic medications, if needed.
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Subjects returned to the site on treatment days 3, 7, and 14. At each visit, the physician repeated the symptom severity ratings and the investigator and the subject separately rated the overall effectiveness of treatment on a scale from 0 ⫽ poor to 10 ⫽ excellent. Subjects were also interviewed regarding the occurrence of any adverse experiences. Statistical Methods Statistical analyses were performed on the pooled data from the three investigational sites. Baseline treatment group comparability was evaluated using the Cochran-Mantel-Haenszel test, controlling for site, for categorical variables (eg, sex, race, medical background) and the two-way analysis of variance (ANOVA), with effects for treatment, site, and treatment-by-site interaction, for variables with continuous distribution (eg, age, weight). Individual symptom scores were summed to create a total symptom score for each treatment group for each visit. As a separate group, the individual symptom scores for the nasal-related allergy symptoms of rhinorrhea, sneezing, and nasal blockage were also summed to create total symptom scores for each group for each visit. Mean scores were calculated for the physician and subject global assessments. For each of these variables, overall comparability of the treatment groups and pairwise comparisons were analyzed using the Cochran-MantelHaenszel test, controlling for site, using modified ridit scores. Adverse event frequencies were compared using Fischer’s Exact test. Statistical significance was declared if the probability of an observed difference being due to random occurrence was ⱕ.05.
RESULTS Study Population A total of 287 eligible subjects were enrolled. The average age of the study population was 39 years (range: 15 to 81 years); 196 were women and 91
were men. The majority of subjects (61.6%) had histories of both seasonal and perennial rhinitis. In 89% of subjects, the nasal mucosa was red and swollen; 10.8% of subjects had complete nasal obstruction. Randomization resulted in the following group sizes: 96 received brompheniramine, 96 received terfenadine, and 95 received placebo. Demographic and baseline characteristics were similar among treatment groups (Table 1). Fifty-seven subjects did not complete the full study period: 32 failed to attend scheduled visits or were unable to comply with the study protocol, 18 had adverse events that precipitated withdrawal from the study; and 7 had intercurrent illnesses. Data from 27 of these 57 subjects, however, were sufficient to be included in the efficacy analyses. As a result, there were 257 subjects analyzed for efficacy: 82 received brompheniramine, 87 received terfenadine, and 88 received placebo. Data from all 287 subjects were included in the analysis for safety. Symptom Severity Figure 1 shows the summed severity scores for all symptoms of allergic rhinitis (ie, rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose or pharynx; excessive lacrimation; and postnasal drip). The three treatment groups were comparable at baseline. Beginning at day 3 and continuing through days 7 and 14, symptom improvement (ie, a decrease in the summed symptom score) was significantly greater in the brompheniraminetreatment group, compared with both the terfenadine-treatment and placebotreatment groups. The decrease in mean summed symptom score among terfenadine-treated subjects was consistently greater than in placebotreated subjects, however, this difference did not achieve statistical significance. The mean individual symptom scores generally paralleled the pattern seen for the summed symptom scores in the three groups (ie, the largest decrease was seen among brompheniramine-treated subjects com-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 1. Baseline Characteristics Brompheniramine Maleate, 12 mg (N ⴝ 96)
Terfenadine, 60 mg (N ⴝ 96)
Placebo (N ⴝ 95)
31 /65 39.6 16–79 167.4 142.2–193.0 70.9 43.6–109.1
27 /69 39.4 15–74 168.4 152.4–188.0 74.5 39.5–143.2
33 /62 37.9 15–81 169.2 144.8–188.0 75.9 47.3–141.8
21 (21.9%) 12 (12.5%) 63 (65.6%)
18 (18.8%) 19 (19.8%) 59 (61.5%)
23 (24.2%) 17 (17.9%) 55 (57.9%)
0 34 (35.4%) 47 (49.0%) 15 (15.6%)
0 32 (33.3%) 56 (58.3%) 8 (8.3%)
0 35 (36.8%) 52 (54.7%) 8 (8.4%)
Male/females Mean Age, yr Range Mean height, cm Range Mean weight, kg Range Current rhinitis type Seasonal (hay fever) Perennial Both Nasal mucosa Normal Slightly swollen, red Very swollen Total obstruction
pared with both terfenadine-treated subjects or those taking placebo). The summed scores for the nasal symptoms cluster (ie, rhinorrhea, sneezing, blockage) are presented in Table 2. Improvement in these nasal symptoms was significantly greater in the brompheniramine-treated subjects than in the terfenadine-treated and placebo-treated subjects at 3, 7, and 14 days. Similar to the results seen with the summed score for all symptoms, the improvement in nasal symptoms in the terfenadine-treatment group was greater than in the placebo group, however, this difference did not reach statistical significance. Overall Treatment The results of the physician’s assessment of overall treatment efficacy (Table 3) demonstrated that brompheniramine had significantly better ratings at days 3, 7, and 14 than terfenadine and placebo. The results for terfenadine were significantly better than placebo at day 14. The subject’s assessment of overall treatment efficacy at days 3, 7, and 14 demonstrated that brompheniramine-treated subjects rated their medication as significantly more effective than did those receiving either terfenadine or placebo (Table 4); on day
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14, the difference between terfenadinetreated and placebo-treated subjects approached statistical significance (P ⫽ .07). Safety One or more adverse experiences were reported by 166 (57.8%) of the 287 subjects who received study medica-
tion (Table 5). A significantly greater (P ⱕ .05) number of brompheniramine-treated subjects (70.8%) reported adverse events, compared with terfenadine-treated subjects (53.1%) and placebo-treated subjects (49.5%). Symptoms related to the central nervous system or to the body as a whole were the most frequently reported in all treatment groups. Somnolence and headache were the most common specific adverse events. Somnolence was reported significantly more frequently among brompheniramine-treated subjects (41.7%) compared with terfenadine-treated subjects (9.4%) or to those receiving placebo (10.5%). Reports of somnolence tended to be less frequent as treatment continued (Table 6). Headache was reported significantly more frequently among terfenadinetreated subjects (28.1%) compared with brompheniramine-treated subjects (14.6%). Eighteen subjects withdrew from the study due to adverse experiences. A significantly (P ⱕ .05) greater number of brompheniramine-treated subjects (12) withdrew due to adverse experiences, compared with terfenadinetreated subjects (3) and placebo-treated subjects (3). The most frequent ad-
Figure 1. Summed symptom score over time for allergic rhinitis patients treated with extended-release brompheniramine 12 mg bid (N ⫽ 82), terfenadine 60 mg bid (N ⫽ 87), and placebo (N ⫽ 88). Summed score includes individual ratings for rhinorrhea; sneezing; ocular pruritus; nasal pruritus; pharyngeal pruritus; excessive lacrimation; and postnasal drip. **P ⱕ .01 vs placebo. ***P ⱕ .001 vs placebo. ⫹P ⱕ .05 vs terfenadine.
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Table 2. Nasal symptoms cluster* summed severity scores (mean ⫾ SD)
Baseline Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 82)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.6 ⫾ 2.6 3.1 ⫾ 2.2†‡ 2.8 ⫾ 2.1†㛳 2.4 ⫾ 2.1§㛳
6.2 ⫾ 2.4 4.0 ⫾ 2.7 3.9 ⫾ 2.8 3.6 ⫾ 2.8
6.2 ⫾ 2.3 4.5 ⫾ 2.8 4.0 ⫾ 2.6 3.9 ⫾ 2.9
* Rhinorrhea, sneezing, nasal blockage. † P ⱕ .01 vs placebo. ‡ P ⱕ .05 vs terfenadine. § P ⱕ .001 vs placebo. 㛳 P ⱕ .01 vs terfenadine. Table 3. Physician’s Global Evaluation* (mean ⫾ SD)
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 81)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.4 ⫾ 2.5†§ 6.9 ⫾ 2.4‡§ 7.7 ⫾ 2.0†§
4.7 ⫾ 3.0 5.5 ⫾ 2.9 6.3 ⫾ 2.8㛳
4.6 ⫾ 3.1 5.4 ⫾ 3.3 5.4 ⫾ 3.4
* Scale: 0 ⫽ poor to 10 ⫽ excellent. † P ⱕ .001 vs placebo. ‡ P ⱕ .01 vs placebo. § P ⱕ .01 vs terfenadine. 㛳 P ⱕ .05 vs placebo.
verse experience necessitating withdrawal from the study prematurely was somnolence in brompheniraminetreated subjects and headache among subjects taking terfenadine. DISCUSSION Antihistamines are widely accepted as effective in the management of symptoms of allergic rhinitis and numerous agents are available both by prescription and over the counter. The newer second-generation H1 antagonists are considered to have an improved riskbenefit ratio compared with their predecessors. Nevertheless, many of the first-generation medications are highly effective and may offer greater advantage to the patient. To our knowledge, this trial is the first reported comparison of nonprescription brompheniramine, in an extended-release formulation, and terfenadine, a second-generation pre-
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scription antihistamine. The purpose of the study was to compare the effects of treatment in subjects with moderate to severe symptoms of allergic rhinitis, utilizing the recommended adult doses (ie, brompheniramine 12 mg twice a day and terfenadine 60 mg twice a day). All subjects entered the current study with moderate to severe symp-
toms and by day 3 of treatment brompheniramine-treated subjects showed significant improvement in symptom severity compared with those in the terfenadine-treatment or placebotreatment groups. Compared with terfenadine-treated subjects, brompheniramine-treated subjects continued to show significant improvement throughout the 14-day study period. The effectiveness of brompheniramine was also evident in the results of the global evaluations. Both physicians and subjects considered brompheniramine to be significantly more effective than terfenadine. This study demonstrates that a classic alkylamine antihistamine, such as brompheniramine, can provide significant relief of allergic rhinitis symptoms. Furthermore, these results demonstrate that nonprescription, extended-release brompheniramine provides greater relief compared with prescription terfenadine. Further, these results are consistent with those of other clinical trials where terfenadine has been reported to be superior to placebo, but not significantly more effective than other first-generation antihistamines.13–16 First-generation antihistamines are historically associated with sedative effects. Not surprisingly, in this trial, subjects taking brompheniramine reported sedation significantly more frequently than terfenadine-treated subjects. Of note, however, the frequency of somnolence reports lessened over time. Headache occurred significantly
Table 4. Subjects’ Global Evaluation* (mean ⫾ SD)
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg (N ⴝ 81)
Terfenadine, 60 mg (N ⴝ 87)
Placebo (N ⴝ 88)
6.0 ⫾ 2.6†‡ 6.5 ⫾ 2.5§‡ 7.4 ⫾ 2.2†‡
4.8 ⫾ 2.9 5.2 ⫾ 3.0 5.7 ⫾ 3.1㛳
4.1 ⫾ 3.0 5.0 ⫾ 3.1 4.9 ⫾ 3.3
* Scale: 0 ⫽ poor to 10 ⫽ excellent. † P ⱕ .001 vs placebo. ‡ P ⱕ .01 vs terfenadine. § P ⱕ .01 vs placebo. 㛳 P ⫽ .07 vs placebo.
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Table 5. Adverse Events Brompheniramine Maleate, 12 mg (N ⴝ 96)
Terfenadine, 60 mg (N ⴝ 96)
Placebo (N ⴝ 95)
17 7 56 2 5 0 1 3 0 68
28 7 20 1 7 3 0 3 0 51
23 6 21 1 5 1 2 0 1 47
Body as a whole Gastrointestinal Nervous*† Skin Respiratory Cardiovascular Genitourinary Special Senses Musculoskeletal Subjects reporting any event‡ * P ⬍ .01 among treatment groups. † See Table 6. ‡P ⬍ .05 among treatment groups.
Table 6. Proportion of Subjects Reporting Somnolence
Day 3 Day 7 Day 14
Brompheniramine Maleate, 12 mg
Terfenadine, 60 mg
Placebo
40% 27% 24%
10% 7% 4%
10% 9% 5%
more frequently among the terfenadine-treated subjects compared with brompheniramine-treated subjects. This increased frequency of headache associated with terfenadine has also been reported in other comparative clinical trials13,15 as well as in terfenadine prescribing information.17 Efficacy and side-effect profiles play important roles in how physicians and their patients choose an antihistamine. In an era of increasingly constrained healthcare resources, consideration of relative cost may also guide the selection of optimal allergic rhinitis treatment. By way of example, the 14day study regimen, based on the average 1995 wholesale cost, would amount to $6.83 for brompheniramine (12 mg bid); the corresponding cost for terfenadine (60 mg bid) is $25.76.18 This study’s data confirm the wellknown finding from controlled clinical trials that first-generation antihistamines are associated with an increased
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frequency of sedation compared with placebo or a nonsedating antihistamine. The data also point out a frequently overlooked corollary—many people can tolerate a first-generation antihistamine without sedation. Nonprescription antihistamine class labeling contains warnings against use of these products in situations where the risk of a sedative potential with a firstgeneration antihistamine like brompheniramine may outweigh any corresponding benefit. The occurrence of somnolence or performance impairment in an individual patient should suggest that an alternative agent could be a more appropriate clinical choice for that individual. Nonetheless, the results of this study demonstrate that symptom relief can be obtained from extended-release brompheniramine without the attendant costs of prescribing or dispensing a prescription antihistamine.
ACKNOWLEDGMENTS We thank Howard Hassman, DO, of Family Practice Associates, San Diego, CA, for his participation in this study. We thank Mr. Lawrence Marinucci from Whitehall-Robins, Madison, NJ, for providing statistical analyses and Ms. Barbara Stern for assistance in the preparation of this manuscript. REFERENCES 1. Naclerio RM. Allergic rhinitis. N Engl J Med 1991;325:860 –9. 2. Kaliner MA. Allergic rhinitis. In: Mygind N, Naclerio RM, eds. Allergic and non-allergic rhinitis. Clinical aspects. Philadelphia: W B Saunders, 1993:153– 8. 3. Badhwar AK, Druce HM. Allergic rhinitis. Med Clin N Am 1992;76: 789 – 803. 4. Simons FER. H1-receptor antagonists. Comparative tolerability and safety. Drug Safety 1994;10:350 – 80. 5. Meltzer EO. Comparative safety of H1 antihistamines. Ann Allergy 1991;67: 625–33. 6. Simons FER, Simons KJ. Secondgeneration H1-receptor antagonists. Ann Allergy 1991;66:6 –19. 7. Drouin MA. H1 antihistamines: Perspective on the use of the conventional and new agents. Ann Allergy 1985;55: 747–52. 8. Kaliner MA, Check WA. Non-sedating antihistamines. Allergy Proc 1988; 9:649 – 61. 9. Lipman WH. The clinical evaluation of parabromdylamine maleate. Ann Allergy 1959;17:19 –24. 10. Schiller IW, Lowell FG. Further use of color coding in drug evaluations; parabromdylamine in perennial allergic rhinitis. N Engl J Med 1959;261: 478 – 82. 11. Grater WC. Comparative effectiveness of two antihistamines in allergic rhinitis. Arch Otolaryngol 1960;72:63–5. 12. MacLaren WR. Parabromdylamine maleate, chlorprophenpyridine maleate and tripelennamine hydrochloride in chronic allergic rhinitis. J Allergy 1959;30:235– 40. 13. Kemp JP, Buckley CE, Gershwin ME, et al. Multicenter double-blind, placebo-controlled trial of terfenadine in seasonal allergic rhinitis and conjunctivitis. Ann Allergy 1985;54:502–9.
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14. Buckley CE, Buchman E, Falliers CJ, et al. Terfenadine treatment of fall hay fever. Ann Allergy 1988;60:123– 8. 15. McTavish D, Goa KL, Ferrill M. Terfenadine. An updated review of its pharmacological properties and therapeutic efficacy. Drugs 1990;39: 552–74.
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16. Brostoff J, Lockhart JDF. Controlled trial of terfenadine and chlorpheniramine maleate in perennial rhinitis. Postgrad Med J 1982;58:422–3. 17. Physicians’ Desk Reference. Montvale, NJ: Medical Economics 1995:1430. 18. 1995 Drug Topics Red Book.
Montvale, NJ: Medical Economics 1995;409,540. Address correspondence to: Sandy A. Furey, PhD, MD. Whitehall Robins Healthcare Five Giralda Farms Madison, NJ 07940
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