SCH 434: A new antihistamine/decongestant for seasonal allergic rhinitis William W. Storms, MD, Stephen F. Bodman, MD, Robert A. Nathan, MD, Paul Chervinsky, MD, Charles H. Banov, MD, Robert J. Dockhorn, MD, Irene Jarmoszuk, MD, Howard J. Zeitz, MD, Stephen J. McGeady, MD, Jacob L. Pinnas, MD, and Saul Greenstein, MD Colorado Springs, Colo.; New Bedford, Mass.; Charleston, S.C.; Prairie Village, Kan.; Chicago, Ill.; Philadelphia, Pa.; Tucson, Ariz.; and Kenilworth, N.J. In a d,ouble-blind, multicenter study, we compared the effects of SCH 434 (Claritin-D; Schering Corp., Kenilworth, N.J.), a new sustained-release, combination antihistamineldecongestant medication, with the effects of its individual components and placebo in 435 patients with seasonal allergic rhinitis. SCH 434 contains 5 mg of loratadine, a nonsedating antihistamine, and I;!0 mg of pseudoephedrine as the decongestant component. Administered twice daily in this study, SCH 434 effected a 50% decrease in total symptom scores at day 4 and was significantly (p 5 0.03) more effective than the components alone or the placebo. Loratadine or pseudoephedrine alone, with 43% and 33% decline in symptom scores, respectively, also was more effective than placebo (p < 0.05). As expected, pseudoephedrine alone was more effective than loratadine (p < 0.01) in relieving nasal stufjiness; SCH 434 was more effective (p 5 0.01) than placebo and loratadine in relieving nasal stuffiness. All treatments were safe and well tolerated, although insomnia and dry mouth were noted in a signijcant number of patients who received either SCH 434 or pseudoephedrine. No serious side effects were noted. The inci&nce of sedation did not differ significantly among the four treatment groups. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis. The combination drug (,SCH 434) was better than its components for some, but not all, symptoms. (J ALLERGY CLINhMUNOL 1989;83:1083-90.) SCH 434 is a combination of 5 mg of loratadine, a nonsedating antihistamine, and 120 mg of pseudo- ephedrine as a decongestant, in a Repetab (Schering Corp., Kenilworth, N.J.) tablet formulation. The immediate-release coating of this tablet contains 5 mg of loratadine and 60 mg of psuedoephedrine. The sustained-release core of the tablet contains 60 mg of pseudoephedrine. Loratadine, a diarylcycloheptane derivative, which is structurally related to azatadine, has potent H,- antihistamine activity’-3 without sedative, anticholin- ergic, or HZ-receptor blocking activity.4-7 Loratadine has a rapid onset of action (2 hours) in suppression of histamine-induced skin wheals.’ Pharmacokinetic studies8-‘ohave demonstrated that From the W. C. Service Allergy and Asthma Research Foundation, Colorado Springs, Cola. Supported by a grant from Schering Corp., Kenilworth, N.J. Received for publication May 9, 1988. Revised Nov. 16, 1988 Accepted for publication Nov. 16, 1988. Reprint requests: William W. Storms, MD, 2709 N. Tejon St., Colorado Springs, CO 80907. loratadine is absorbed well after an oral dose, with peak plasma levels 1 hour after dose. Loratadine un- dergoes extensive first-pass metabolism. The elimi- nation half-life is 15 hours. Forty percent of an oral dose is excreted in the urine and 40% in the feces. The results of pharmacokinetic studies in healthy ge- riatric volunteers and in young adults are identical (Schering Corp. Personal communication). Breast milk levels of loratadine in healthy, nonpregnant lac- tating volunteers were similar to plasma levels; total excretion of loratadine in breast milk represented 0.03% of the orally administered dose (Schering Corp. Personal communication). Clinical studies73 ‘l-l3 have demonstrated that lora- tadine is more effective than placebo and as effective as terfenadine, astemizole, clemastine, and mequita- zine for the treatment of seasonal allergic rhinitis. In those studies, loratadine effectively relieved the symp- toms of allergic rhinitis (sneezing, nasal pruritus, and nasal discharge) within 4 hours. The present study was conducted to evaluate the effects of loratadine alone and in combination with a decongestant (pseudoephedrine) in patients with sea- sonal allergic rhinitis. Combination formulations of 1083
Transcript
SCH 434: A new antihistamine/decongestant for seasonal allergic rhinitis
William W. Storms, MD, Stephen F. Bodman, MD, Robert A. Nathan, MD, Paul Chervinsky, MD, Charles H. Banov, MD, Robert J. Dockhorn, MD, Irene Jarmoszuk, MD, Howard J. Zeitz, MD, Stephen J. McGeady, MD, Jacob L. Pinnas, MD, and Saul Greenstein, MD Colorado Springs, Colo.; New Bedford, Mass.; Charleston, S.C.; Prairie Village, Kan.; Chicago, Ill.; Philadelphia, Pa.; Tucson, Ariz.; and Kenilworth, N.J.
In a d,ouble-blind, multicenter study, we compared the effects of SCH 434 (Claritin-D; Schering Corp., Kenilworth, N.J.), a new sustained-release, combination antihistamineldecongestant medication, with the effects of its individual components and placebo in 435 patients with seasonal allergic rhinitis. SCH 434 contains 5 mg of loratadine, a nonsedating antihistamine, and I;!0 mg of pseudoephedrine as the decongestant component. Administered twice daily in this study, SCH 434 effected a 50% decrease in total symptom scores at day 4 and was significantly (p 5 0.03) more effective than the components alone or the placebo. Loratadine or pseudoephedrine alone, with 43% and 33% decline in symptom scores, respectively, also was more effective than placebo (p < 0.05). As expected, pseudoephedrine alone was more effective than loratadine (p < 0.01) in relieving nasal stufjiness; SCH 434 was more effective (p 5 0.01) than placebo and loratadine in relieving nasal stuffiness. All treatments were safe and well tolerated, although insomnia and dry mouth were noted in a signijcant number of patients who received either SCH 434 or pseudoephedrine. No serious side effects were noted. The inci&nce of sedation did not differ significantly among the four treatment groups. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis. The combination drug (,SCH 434) was better than its components for some, but not all, symptoms. (J ALLERGY CLINhMUNOL 1989;83:1083-90.)
SCH 434 is a combination of 5 mg of loratadine, a nonsedating antihistamine, and 120 mg of pseudo- ephedrine as a decongestant, in a Repetab (Schering Corp., Kenilworth, N.J.) tablet formulation. The immediate-release coating of this tablet contains 5 mg of loratadine and 60 mg of psuedoephedrine. The sustained-release core of the tablet contains 60 mg of pseudoephedrine.
Loratadine, a diarylcycloheptane derivative, which is structurally related to azatadine, has potent H,- antihistamine activity’-3 without sedative, anticholin- ergic, or HZ-receptor blocking activity.4-7 Loratadine has a rapid onset of action (2 hours) in suppression of histamine-induced skin wheals.’
Pharmacokinetic studies8-‘o have demonstrated that
From the W. C. Service Allergy and Asthma Research Foundation, Colorado Springs, Cola.
Supported by a grant from Schering Corp., Kenilworth, N.J. Received for publication May 9, 1988. Revised Nov. 16, 1988 Accepted for publication Nov. 16, 1988. Reprint requests: William W. Storms, MD, 2709 N. Tejon St.,
Colorado Springs, CO 80907.
loratadine is absorbed well after an oral dose, with peak plasma levels 1 hour after dose. Loratadine un- dergoes extensive first-pass metabolism. The elimi- nation half-life is 15 hours. Forty percent of an oral dose is excreted in the urine and 40% in the feces. The results of pharmacokinetic studies in healthy ge- riatric volunteers and in young adults are identical (Schering Corp. Personal communication). Breast milk levels of loratadine in healthy, nonpregnant lac- tating volunteers were similar to plasma levels; total excretion of loratadine in breast milk represented 0.03% of the orally administered dose (Schering Corp. Personal communication).
Clinical studies73 ‘l-l3 have demonstrated that lora- tadine is more effective than placebo and as effective as terfenadine, astemizole, clemastine, and mequita- zine for the treatment of seasonal allergic rhinitis. In those studies, loratadine effectively relieved the symp- toms of allergic rhinitis (sneezing, nasal pruritus, and nasal discharge) within 4 hours.
The present study was conducted to evaluate the effects of loratadine alone and in combination with a decongestant (pseudoephedrine) in patients with sea- sonal allergic rhinitis. Combination formulations of
1083
1064 Storms et al. J. ALLERGY CLIN. IMMUNOL. JUNE 1989
antihistamines and decongestants are used frequently in the clinical practice of allergy. There is a question whether such combinations are more efficacious than their individual components.
METHODS Seven centers participated in this double-blind, parallel-
group study comparing the efficacy and safety of SCH 434 (loratadine, 5 mg, and pseudoephedrine, 120 mg), lorata- dine alone, pseudoephedrine alone, and placebo in 435 pa- tients with seasonal allergic rhinitis. The study protocol and an informed consent statement were approved by the Insti- tutional Review Board for each individual study site; each patient signed an informed-consent statement.
Patients were screened at the baseline visit and were required to have moderate to severe symptoms of seasonal allergic rhinitis, positive allergy skin tests with extracts of appropriate seasonal allergens, and a history compatible with seasonal allergic rhinitis of at least 2 years duration. The study was conducted during the grass and/or weed season at each study center. Patients were enrolled only if they were expected to have symptoms during the entire treatment trial (August to October). Before dosing, pa- tients were required tso stop taking oral nasal decongestants (for 24 hours), oral antihistamines (for 48 hours), topical corticosteroids, nasal or ocular topical treatment, cromolyn (for 2 weeks), or systemic corticosteroids (for 1 month). These treatments also were prohibited during the entire study. Patients with upper respiratory tract infections and other significant medical conditions were excluded from the study.
Patients enrolled in the study were assigned by a computer-generated random code to one of four treatment groups: SCH 434 (loratadine, 5 mg, and pseudoephedrine,
120 mg), loratadine, 5 mg, pseudoephedrine, 120 mg, or placebo. SCH 434 was supplied as a tablet, loratadine as a capsule, pseudoephedrine as a tablet, and placebo as a tablet or a capsule. A double-dummy technique was used so that each patient received one tablet and one capsule, twice daily. Each medication was administered twice daily for 14 days. Patients were evaluated by a physician on days 4, 8, and 15. All patients kept a daily diary of symptom scores in which they recorded the severity of their symptoms between visits.
Individual symptoms of allergic rhinitis were recorded by each patient on a diary card before entry and during the treatment phase. Additionally, an overall global evaluation of therapeutic response to treatment was made by both the physician and the patient at each follow-up visit with a rating scale of 1 to 5 (1, excellent; 5, treatment failure).
The nasal symptoms evaluated included discharge, stuf- finess, sneezing, and pruritus. Nonnasal symptoms, includ- ing ocular pruritus, tearing and redness of the eyes, and itching of the ears and/or palate, also were evaluated. Each individual’s symptoms were scored for severity as follows: 0, none; 1, mild; 2, moderate; and 3, severe. The total symptom s#everity score was the sum of all eight individual symptom scores; the nonnasal score was the sum of the four nonnasal symptoms, and the nasal score was the sum of the four nasal symptoms. On entry into the study (baseline day), patients were required to have a score of at least 2 for discharge and at least 2 for stuffiness, a nasal symptom score of at least 6, and a nonnasal symptom score of at least 5.
Evaluation of safety was based on assessment of clinical observations relative to baseline. Within 7 days before treat- ment initiation, the general health of each patient was as- sessed through medical and allergy histories, a physical examinaton, and laboratory tests (complete blood cell count,
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New antihistamine/decongestant 1085
80
70 F
l SCH 434 II Pseudoephedrine
q Loratadine C] Placebo 60
50 Percent
Improvement 4o
30
20
10
0 -Day 4+ +-End Point-
FIG. 1. Percent improvement in mean total symptoms. Surr of nasal discharge, stuffiness, itching, sneezing, itching/burning eyes, tearing, redness, itching ofearslpalate. At day4: SCH 434versus loratadine, p = 0.03; SCH 434 versus pseudoephedrine and placebo, p = CO.01 ; at end point: SCH 434 versus loratadine, p = 0.19; and SCH 434 versus pseudoephedrine and placebo, p = co.05.
blood chemistries, and urinalysis). The laboratory tests were repeated at study completion. Any clinically meaningful changes from baseline and their relationship to treatment (probable, possible, or unrelated) were noted. At each treat- ment visit, any adverse experiences described by the patients or recorded on the daily diaries were noted.
Statistical analysis
For the pooled area from all centers, efficacy parameters were analyzed with the two-way analysis of variance model with SAS type III sums of squares. Pair-wise comparisons between any two treatment groups were performed with the least-square means results from the two-way analysis of variance. The individual symptoms in the overall ther- apeutic responses were additionally analyzed with categoric linear models to confirm the results of the analysis of variance.
Efficacy analyses were performed on the data obtained at each visit and on the combined data obtained from the last valid visit for each patient (i.e., the end point of treat- ment for all patients). The end point analysis compensates for lost data caused by early terminations and missed or unevaluable visits,
The incidence of all adverse experiences and specific adverse experiences were analyzed with the Fisher’s exact test extended for 2 x 4. A 2 x 2 Fisher’s exact test was used to test pair-wise treatment group comparisons.
RESULTS Demographics
Of the 444 patients enrolled, two patients had no data after baseline visit and were excluded from all analyses. Seven additional patients were excluded from the efficacy analyses for the entire study because of protocol violations. Thus, 442 patients were in- cluded in the safety population and 435 in the efficacy
population (Table I). There were no significant dif- ferences between any two of the treatment groups with regard to gender, race, age, weight, or duration of rhinitk.
Total symptom severity
At baseline, the groups had equivalent mean total symptom scores; there were no statistically significant differences among the four treatment groups. By day 4, the mean total symptom scores decreased from baseline by 51%, 42%, 38%, and 28% for the SCH 434-, loratadine-, psuedoephedrine-, and placebo- treatment groups, respectively (Fig. 1). The 56% im- provement in the SCH 434-treatment group on day 4 was significantly greater (p I 0.03) than the im- provement in all other treatment groups. Loratadine and pseudoephedrine were significantly more effective (p 5 0.02) than placebo.
By the last visit (end point), the mean total symp- tom score had decreased by 55% in the SCH 434- treatment group compared with decreases of 50%, 46%, and 38% in the loratadine-, pseudoephedrine-, and placebo-treatment groups, respectively (Fig. 1). The improvement in the SCH 434-treatment group at end point was significantly greater (p 5 0.05) than that in the placebo- and pseudoephedrine-treatment groups. The mean total symptom decrease with lo- ratadine was significant (p 5 0.01) when loratadine was cclmpared with placebo at end point.
Total nasal symptoms
All four groups began the study with similar mean total nasal symptom scores. On day 4, the mean total nasal symptom score decreased 48% for the SCH 434-
1088 Storms et al. J. ALLERGY CLIN. IMMUNOL. JUNE 1969
80
t
n SCH 434 q Pseudoephedrine
70 &j Loratadine 0 Placebo
60
50
Percent 4. Improvement
30
20
10
0 I --Day 4-l E-End Point __(
FIG. 2. Percent improvement in nasal itching. At day 4: SCH 434 versus pseudoephedrine and placebo, p = <O.Ol; at end point: SCH 434 versus placebo, p = <O.Ol.
n SCH 434
q Loratadine
Pseudoephedrine
0 Placebo
60
Percent 4. Improvement
30
20
10
0
V-Day 4-i f--End Point +
FIG. 3. Percent improvement in nasal discharge. At day 4: SCH 434 versus loratadine, pseu- doephedrine, and placebo, p = cO.01; at end point: SCH 434 versus placebo, p = cO.01.
treatment group, compared with 34%, 35%, and 24%, for the loratadine-, pseudoephedrine-, and placebo- treatment groups. The 48% decrease with SCH 434 was significantly greater (p or 0.01) than the de- creases in all other treatment groups. Decreases in nasal symptom scores with loratadine and pseudo- ephedrine alone we.re significant (p I 0.02) when these were compared with placebo.
At end point, the mean totai nasal symptom score was reduced 49% in the SCH 434-treated group, compared with 43% in the loratadine- and pseudoephedrine-tread groups and 33% in the placebo-treated group. The decrease with SCH 434 was singificantly greater (p 5 0.01) than with pla- cebo, as were the decrases with loratadine and pseu- doephedrine (p d 0.05). The difference between SCH 434 and loratadine treatment at the end point tended toward significance (p = 0.09).
Total nonnasal symptoms
The mean total nonnasal symptom scores (sum of eye itching, eye tearing, eye redness, and itching of ears and/or palate) at baseline were similar among the four treatment groups. Decreases in scores from baseline on day 4 were 53% with SCH 434 and lo- ratadine, 4,1% with pseudoephedrine, and 34% with placebo. At the last visit, the decreases in the mean total nonnasal symptom scores were 62%) 60%) 49%) and 46%, respectively. At both day 4 and at end point, the improvement from baseline with SCH 434 treat- ment was significantly greater (p 5 0.01) than with placebo and pseudoephedrine. The improvement with loratadine treatment was significant (p : 0.01) com- pared with placebo at both day 4 and at the last visit. Pseudoephedrine treatment was not significantly dif- ferent from placebo in reducing nonnasal symptoms at either evaluation. When the individual nonna-
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New antihistamine/decongestant 1087
TABLE II. Physicians’ global evaluation of response to treatment (mean score*)
Visit SCH 434 Loratadine Pseudoephedrine Placebo
Day 4 2.4t 2.8 2.9 3.2 Day 8 2.5 2.8 2.6 3.0 Day 15 2.4 2.6 2.5 2.8 End point 2.5$ 2.73 2.7$ 3.0
*Response was rated as 1, excellent; 2, good; 3, fair; 4, poor; 5, treatment failure. tSCH 434 versus loratadiie, pseudoephedrine, and placebo, p = <O.Ol $SCH 434, loratadine, and pseudoephedrine versus placebo, p = ~0.03.
Treatment failure 6 7 8 12 Adverse experience 0 2 8* 1 Intercurrent illness 1 4 0 1 Noncompliance or other protocol violation 0 2 1 2 Did not wish tab continue 0 1 0 0 Personal (not study related) 0 1 0 1 Total 7t 17 17 17
*Significantly greater than SCH 434 @ = 0.01) and placebo @ = 0.04). Wgnificantly fewer than loratadine (p = 0.05), pseudoephedrine @ = 0.05), and placebo (p = 0.04).
sal symptoms were observed, SCH 434 treatment was better than both pseudoephedrine and placebo (p < 0.05) for eye itching and tearing at days 4 and end point, and for itchy ear/palate at day 4. There was no change regarding eye redness.
Nasal stuffmess
The percent improvement in the mean nasal stuf- finess scores were not significantly different at base- line for the four treatment groups. On day 4 the mean nasal stuffiness lscore for the SCH 434-treated group decreased from baseline by 42% compared wth de- creases of 22%., 38%, and 28% in the loratadine-, pseudoephedrine-, and placebo-treated groups, re- spectively. This decrease in the mean score with SCH 434 treatment was significantly greater (p 5 0.01) than with placebo and loratadine, and not statisti- cally different from pseudoephedrine. Pseudoephe- drine alone was significantly better than loratadine (p 5 0.01) and marginally better than placebo (p = 0.07).
At end point, the decreases were 42% in the SCH 434-treated and pseudoephedrine-treated groups, 35% in the loratadine-treated group, and 28% in the pla- cebo-treated group. The improvement in stuffiness at
the last visit with SCH 434 or pseudoephedrine treat- ment was significantly greater (p = 0.05) than with placebo. Loratadine was not different from placebo in decreasing nasal stuffiness.
Nasal itching
Nasal itching improved significantly in the SCH 434-treated group (Fig. 2). At day 4, the percent improvement in symptoms was 50% for SCH 434, 37% for loratadine, 35% for pseudoephedrine, and 21% for placebo. At end point, the changes were 55%, 42%, 45% and 32%, respectively. SCH 434 was significantly better than placebo for nasal itching (p < 0.01) at both day 4 and end point.
Nasal discharge
SCH 434 was effective in relieving nasal discharge (Fig. 3). The percent improvement in nasal drainage at day 4 was 46% for SCH 434, 33% for loratadine, 33% for pseudoephedrine, and 28% for placebo. At end point, the percent improvement was 42%, 46%, 42%, and 30%, respectively. SCH 434 treatment was significantly better (p < 0.01) than loratadine, pseu- doephedrine, and placebo at day 4. SCH 434 was better (p < 0.01) than placebo at end point.
1088 Storms et al. J. ALLERGY CLIN. IMMUNOL. JUNE 1989
TABLE IV. Treatment-related adverse experiences with 2 5% incidence
No. of patients
SCH 434 (N = 111)
Loratadine (N = 112)
Pseudoephedrine (N = 111)
Placebo (N = 108)
No. of patients reporting treatment-relatecl ad- verse experiences
Central and peripheral nervous system Sedation Dizziness Insomnia Nervousness Dry mouth
General disorders Fatigue Headache
66 (59)*i
9 (8) 4 (4)
21 (19)*t 6 (5)
27 (24)*tf
5 o)* 10 (9)
42 (38)
8 (7) 1 (1) 4 (4) 4 (4) 6 (5)
11 (lo)*$ 17 (15)
55 (50) 39 (36)
9 (8) 5 (5) 6 (5) 2 (2)
19 (17)*t 3 (3) 8 (7) 2 (2)
13 (12)*t 4 (4)
2 (2) 0 (0) 11 (10) 21 (2O)G
*Significantly greater than placebo. tSignificantly greater than loratadine. $Signiticantly greater than pseudoephedrine. $Significantly greater than SCH 434.
Eye itching
Itching of the eye:s is an important nonnasal symp- tom that occurs in patients with allergic rhinitis. SCH 434 was effective in relieving this symptom. The per- cent improvement at day 4 was 55% for SCH 434, 55% for loratadine, 41% for pseudoephedrine, and 33% for placebo. At end point the percent improve- ment was 64% for SCH 434,64% for loratadine, 50% for pseudoephedrine, and 43% for placebo. The im- provement observed with SCH 434 was significant at the p = 0.01 level for both day 4 and at end point.
Physicians’ and patients’ global evaluation of treatment
The mean physician global evaluation of therapeutic response is summarized in Table II. At day 4, the mean physician global evaluation of the SCH 434- treated group was significantly better (p < 0.01) than the global evaluations of the loratadine-, pseudo- ephedrine-, and placebo-treated groups. At end point, the global evaluation of the SCH 434-treated group was not significantly different from the global eval- uation of the loratadine- and pseudoephedrine-treated groups; however, the global evaluation of all three treatment groups was better than that of the placebo- treated group (p < 0.03).
The results of the mean patients’ global evaluation scores were very similar to the physicians’ evalua- tions. At day 4, SCH 434 was significantly more ef- fective than loratadine, pseudoephedrine, or placebo. At end point, all three drugs were better than placebo.
Study dropouts
The number of patients who stopped treatment is presented in Table III. The lowest number of dropouts occurred in the SCH 434-treated group, significantly fewer than in the loratadine-, pseu- doephedrine-, or placebo-treatment groups (all p values, 10.05). Although fewer patients in the SCH 434-treated group stopped because of treatment failure than in the placebo-treated group, this difference was not statistically significant. Eight patients in the pseudoephedrine-treated group stopped because of ad- verse experiences, a statistically significantly differ- ence from the dropout rate in the SCH 434-treated (p = 0.01) and placebo-treated (p = 0.04) groups.
Safety (adverse experiences)
As previously noted in Table III, 11 patients (2% of the study population) stopped the study prematurely because of adverse experiences. None of the patients in the SCH 434-treated group stopped because of an adverse experience, whereas eight patients in the pseudoephedrine-treated group stopped for this rea- son. There were significantly more dropouts in the pseudoephedrine-treated group than in the SCH 434- treated group (p = 0.04) for the placebo-treated group (p y= 0.01).
Treatment-related adverse experiences with a 5% or greater incidence are summarized in Table IV. There was no statistically significant difference between SCH 434 and pseudoephedrine relative to the inci- dence of adverse experiences. However, a signifi-
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New antihistamine/decongestant 1089
cantly greater (p = 0.01) number of adverse expe- riences occurred with SCH 434 than with loratadine or placebo treatment.
The incidence: of sedation with SCH 434 (S%), pseudoephedrine (8%), and loratadine (7%) was sim- ilar to that observed with placebo treatment (5%). All incidents of sedation considered by the investigators to be probably or possibly treatment-related were mild to moderate, with the exception of two patients (one in the SCH 434-treated group and one in the placebo- treated group) who reported severe sedation.
Nervousness, an effect commonly associated with pseudoephedrine, occurred most frequently with pseu- doephedrine alone (7%) but was also noted with SCH 434 (5%). loratadine (4%), and placebo (2%); these differences were not statistically significant. Ner- vousness was reported to be mild or moderate in all cases.
Another adverse experience frequently associated with pseudoephedrine, insomnia, was reported by a significantly greater (p = 0.01) number of patients treated with SCH 434 (19%) and pseudoephedrine (17%) than by those treated with loratadine (4%) or placebo (3%). There was no statistical difference be- tween SCH 434 and pseudoephedrine in the incidence of insomnia.
Dry mouth was reported by significantly more (p = 0.01) SW 434-treated patients (24%) than by patients treated with loratadine (5%), pseudoephe- drine (12%), and placebo (4%). The incidence of dry mouth in patients treated with pseudoephedrine also was significantly greater (p = 0.01) than in patients treated with loratadine and placebo.
There were no clinically significant changes in vital signs, which were recorded throughout the study. The results of the 1;aboratory tests (complete blood cell count, blood chemistries, and urinalysis) did not re- veal any clinically significant differences at the end of the study when results were compared to test results at entrance into the study.
DISCUSSION
Oral antihistamines and decongestants, alone or in combination, are the mainstay of treatment for sea- sonal allergic rhinitis. Previous studies have demon- strated that loratadine is an effective antihistamine for the treatment of seasonal allergic rhinitis.6, 7. I’. ‘* It has been demonstrated to be especially effective in reducing sneezing, nasal discharge, nasal pruritus, and itching/ burning of the eyes, the primary symp- toms of allergic rhinitis. As a medication class, anti- histamines are not known for superior effectiveness in relieving nasal stuffiness. Thus, it is common clin- ical practice to combine a nasal decongestant with an antihistamine to increase the control of allergy symp-
toms. Pseudoephedrine is an effective decongestant that has been marketed for many years. The current study evaluated the effectiveness of a combination of loratadine and pseudoephedrine (SCH 434), each component alone, and placebo.
SCH 434 was more effective than loratadine or pseudoephedrine alone or placebo in relieving many of the symptoms of seasonal allergic rhinitis. At day 4 evaluations, the combination was significantly better than its components in reducing total symptoms, total nasal symptoms, nasal stuffiness, and nasal discharge. As expected, both loratadine and pseudoephedrine alone also were more effective than placebo. Other data in this study did not support the better effect of the combination drug over the components. As an example, the total symptom scores (nasal and non- nasal) for SCH 434 were significantly better for lo- ratadine alone only at day 4, not at end point. This same effect was observed in the analysis of the global evaluations, wherein the combination was more ef- fective than the components only at day 4. This latter fact deserves special note. In recent years there has been a trend away from drugs with more than one ingredient, for various reasons. The data in the current study speak in favor of the combination of loratadine and pseudoephedrine (SCH 434)) since the data dem- onstrate that SCH 434 is a better treatment for allergic rhinitis than either of its components.
In addition to being potentially more effective than single-,entity drugs, combination products offer some practical advantages for patients. First, there is better compliance when a patient has to remember only one pill instead of two. Second, the cost of two separate prescriptions is likely to be more than the cost of one prescription.
The sedative side effects of antihistamines have been well-known for many years. These sedative ef- fects have limited the use of older antihistamines in many patients. Studies of the newer antihistamines also have identified evidence of sedation in the treat- ment groups. Sometimes the incidence has been more frequent in the antihistamine-treated group than in the placebo-treated group, as was the case in a recent study of terfenadine,14 but the differences have not been found to have statistical significance. Thus, some patients who receive these new “nonsedating” anti- histamines will have sedation, although the incidence will be the same as that observed with placebo.
Certain treatment-related adverse experiences were noted during this study. Insomnia was noted in the SCH 434- and pseudoephedrine-treated groups, pre- sumably caused by the sympathomimetic effects of the pseudoephedrine. Dry mouth was noted in the SCH 434- and pseudoephedrine-treated groups. The reason for this side effect is unclear.
1090 Storms et al. J. ALLERGY CLIN. IMMUNOL. JUNE 1989
Previous studies have demonstrated that loratadine has no effect on central nervous system H, receptors, which might well explain the lack of evidence of sed- ative effects.4. ‘. 15, I6 In the present study, the incidence
ative effects of antihistamines. J ALLERGY CLIN IMMUNOL 1987;80:94.
6. Bruttmann G, Pedrali P. Loratadine (SCH 29851) 40 mg once daily vs. terfenadine 60 mg twice daily in the treatment af seasonal allergic rhinitis. J Intern Med Res 1987;15:63.
of sedation was 8% in the SCH 434-treated group, 7% in the antihistamine-treated alone aroun (lorata- dine), 8% in the pseudoephedrine-treated gioup, and 5% in the placebo-treated group.
These findings are comparable to findings observed with other new antihistamines.‘, 7, “, I3
7. Dockhorn RJ,Bergner A, Connell JT, Falliers CJ, Grabiec SV, Weiler J, Shellenberger MK. Safety and efficacy of loratadine (SCH 29851): a new nonsedating antihistamine in seasonal allergic rhmitis. AM Allergy 1987;58:407.
8. Katchen B, Cramer J, Chung M, GuraJ R, Hilbert J, Luc V, Mortizon V, D’Souza R, Symchowicz S, Zampaalione N. Dis- position of %-SCH 29851 in humans. Ann Allergy 1985;
CONCLUSION 55:393.
9. Hilbert J, Radwanski E, Weglein R, Luc V, Perentesis G, Symchowicz S, ZampaglioneN. Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmacol 1987;27: 694-8.
1987;27:530-3.
__ _. 10. Radwanski E, Hilbert J, Symchowicz S, Zampaglione N. Lo-
11. Bruttmann G, Pedrali P. SCH 29851 and the treatment of
seasonal allergic rhinitis (pollinosis) [Abstract]. Ann Allergy 1985;55:233.
In this study the effects of SCH 434 (loratadine plus
I
pseudoephedrine [Claritin-D; Schering Corp., Ken-
I
ilworth , N . J . 1) and each of its components alone were I
comnared to the effects of nlacebo in 435 natients with seasonal allergic rhinitis. SCH 434 was more effective than placebo. The combination also was more effective than its individual ingredients, lora- tadine and pseudoephedrine, in controlling many nasal symptoms after 4 days of use. The incidence of sedation was no greater with SCH 434 than with placebo. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis.
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