Opmaak

Cetirizine and pseudoephedrine retard, givenalone or in combination, in patients with seasonalallergic rhinitis* M. Grosclaude1, K. Mees2, M.E. Pinelli3, M. Lucas3, H. Van de Venne3 Centre Claude Bernard, Guilherand-Granges, France HNO-Klinik Grosshadern, München, Germany UCB S.A. Pharma Sector, Braine-l’Alleud, Belgium We compared the efficacy and safety of cetirizine (5 mg), pseudoephedrine retard (120 mg), and the combination of cetirizine (5 mg) with pseudoephedrine retard (120 mg), each given twice daily for two weeks to subjects with pollen-associated allergic rhinitis. The study was multicentre and of randomized, double-blind, parallel-group design. Five rhinitis symptoms were rated according to severity on a scale of 0-3, daily by patients and at each clinic visit by investigators. A total of 687 patients, aged 9-66 years (mean: 32 years) was randomised to treatment (cetirizine: 231; pseudoephedrine: 226; combination: 230). On entry, the three groups were comparable in relevant respects. The primary outcome measure was based on the five symptoms assessed by the patients over the 2-week treatment period. The combination was more effective, providing at least 20% more “comfortable days” (symptoms absent or at most mild) than cetirizine or pseudoephedrine given alone (median values: 53.3%, 30.8%, and 33.3%, respectively; p<0.001). For nasal obstruction, the combination (mean score: 1.19) was more effective than cetirizine (mean score: 1.43; p=0.0005), but there was little difference between the combination and pseudoephedrine (mean score: 1.22; not significant). Sneezing, rhinorrhoea, nasal and ocular pruritus were better controlled by combination (mean 4-symp- tom score: 0.77) than by pseudoephedrine alone (mean 4-symptom score: 1.12; p<0.001) and also better than by cetirizine alone (mean 4-symptom score: 0.93; p<0.001). No unexpected adverse reactions were observed. A combination of cetirizine and pseudoephedrine retard is well tolerated and superior to each given alone for moderate to severe allergic seasonal rhini- tis, especially when nasal obstruction is a predominant symptom. Keywords: cetirizine, pseudoephedrine, seasonal rhinitis, allergic rhinitis allergic rhinitis (Falliers et al., 1991; Mansmann et al., 1992; Masi The treatment of symptoms of seasonal allergic rhinoconjuncti- et al., 1993; Jobst et al., 1994). Cetirizine is normally taken as a vitis often requires the use of an antihistamine to control symp- single daily dose of 10 mg, but a dose of 5 mg twice daily has been toms primarily mediated by histamine, such as sneezing, shown to be as effective (Wassemlan et al., 1991).
rhinorrhoea, nasal and ocular pruritus, together with a deconge- Relief of nasal congestion by pseudoephedrine, taken orally, is stant to improve nasal congestion when it is a prominent sympt- well documented, both when it is taken alone (Roth et al., 1977; Hamilton et al., 1982) and in combination with an H -antagonist Each new fixed-combination product must be shown to be more agent (Backhouse et al., 1990; Bronsky et al., 1995; Bertrand et effective than its components given as sole therapy. More precise- al., 1996; Dockhorn et al., 1996). The maximal daily dose of ly, the combination must at least provide better control of nasal pseudoephedrine is 240 mg, in adults and children 12 years and obstruction than the antihistamine alone, and be superior to pseu- over, even in over-the-counter products in the United States doephedrine alone in treating the other symptoms of rhinitis.
Cetirizine is a potent, selective H -antagonist of established effica- The present study examined the efficacy and safety of cetirizine cy and good tolerability in the treatment of seasonal and perennial (5 mg) and pseudoephedrine retard (120 mg), each given twice * Received for publication August 1, 1996; accepted November 15, 1996 daily, with a combination formulation of cetirizine and pseu- allergic rhinitis; (2) escalating doses of desensitization therapy; doephedrine in subjects with pollen-associated allergic rhinitis.
and (3) participation in another drug trial during the preceding A placebo group was not considered to be needed as the trial three months. Pregnant or lactating women were not included.
aimed at evaluating the superiority of the combination over Patients who had taken any of the following medications within the periods specified were excluded from entry: (1) astemizole (6 weeks); (2) systemic corticosteroids, ketotifen or MAO inhi- bitors (2 weeks); (3) topical corticosteroids or sedatives (1 week); or (4) nasal decongestants, antihistamines other than The study was multicentre and of double-blind design. Patients astemizole and ketotifen, and nasal or ocular cromoglycate (2 were allocated, in blocks of three, stratified by centre, from a days). Concomitant use of any of these agents during the trial computer-generated randomisation list, to one of three treat- led to withdrawal, as well as other protocol violations, ineffica- ments: 5 mg cetirizine alone; 120 mg pseudoephedrine retard cy, adverse events or personal reasons.
alone; and the same doses of both agents in combination.
Treatment with each regimen was given twice daily for two weeks to subjects with pollen-associated allergic rhinitis. A total Patients were randomized to one of the following treatment of 43 centres participated in the study, 30 in France and 13 in regimens: (1) cetirizine (5 mg) and pseudoephedrine retard Germany. The study was performed between March and placebo; (2) pseudoephedrine retard (120 mg) and cetirizine September 1992, when pollen counts were high (data not placebo; and (3) cetirizine (5 mg) and pseudoephedrine (120 mg). All medications were in capsules of identical appearance The study was conducted in accordance with the amended and taken twice daily with meals. No rescue medication was Declaration of Helsinki (Tokyo, 1991) and the European Community Guidelines on Good Clinical Practice (1990).
Medications prohibited during the study were corticosteroids Patients, their parents or guardians gave their written informed (except inhaled steroids in a dose ≤400 µg/day), sedatives, topic- consent and the study protocol was approved by relevant Ethics al nasal and ocular medications, appetite suppressants, amphe- tamine CNS stimulants, cromones other than by inhalation, The study required three visits of the patient: on entry, review after one week, and a final visit after two weeks’ treatment. Male Medications for the treatment of asthma (theophylline, ß2-sym- and female out-patients (aged 12-65 years) with a documented pathomimetic drugs, inhaled cromoglycate, nedocromil, inha- history of pollen-associated allergic rhinitis for at least one year led corticosteroids in a dose ≤400 µg/day) and non-steroidal and skin or RAST tests positive to seasonal allergens were topical agents for atopic dermatitis could be taken, provided that admitted to the study. Women of childbearing potential had to be using a medically acknowledged method of contraception and a negative pregnancy test was required prior to enrollment.
On entry, all patients presented with nasal obstruction together On entry to the study, the findings from history and physical with at least two of the following symptoms of rhinitis: snee- examination were recorded. On entry, at review one week later zing, rhinorrhoea, nasal pruritus, or ocular pruritus. Symptoms and at the final visit, investigators evaluated the following symp- were scored on a 4-point scale: “0”: absent; “1”: mild (present toms of allergic rhinitis: nasal obstruction, sneezing, rhinor- but not disturbing); “2”: moderate (disturbing but not hampe- rhoea, nasal pruritus, and ocular pruritus - using the 4-point ring daily activities or sleep); and “3”: severe (hampering daily activities and/or sleep). Nasal obstruction on the day of admis- Patients evaluated the same symptoms (sneezing, runny nose, sion was at least moderate in degree (score 2) and the total score blocked nose, itchy nose, and itchy eyes) each day using the for the five symptoms was at least 8 (of a possible 15), indicating same 4-point scale and the results, entered in the patients’ dia- rhinitis of moderate to severe degree.
ries, constituted the primary efficacy variables. At the final Patients to whom any of the following criteria applied were not assessment, the investigator made a global evaluation of the eligible for inclusion: (1) asthma, requiring either a change in effect of treatment using the following 5-point scale: “0”: worse; treatment, or systemic or inhaled corticosteroids in a dose more “1”: no change; “2”: slight improvement; “3”: marked improve- than 400 µg/day; (2) atopic dermatitis or urticaria requiring anti- histamines or systemic or topical corticosteroids; (3) an upper Heart rate and blood pressure were checked at each visit; all respiratory tract infection present on the day of admission; (4) adverse events together with outcome, severity, duration and pos- obstructive nasal polyps or significant septal deviation; (5) rele- sible causal relationship with the study drugs were recorded and vant renal, hepatic or cardiovascular disease requiring treat- classified according to the COSTART dictionary (DHHS, 1989).
ment; (6) hypertension; (7) hyperthyroidism; (8) diabetes; (9) Blood was taken for routine laboratory safety tests (full blood glaucoma; (10) prostatic hypertrophy; (11) urinary retention; count, haematocrit, SGOT, SGPT, total serum bilirubin, blood (12) hypersensivity to cetirizine or pseudoephedrine; and (13) urea, and plasma creatinine) at the first and last visits.
an infection requiring antibiotic treatment. Other reasons for Returned tablets were counted to determine compliance with exclusion were: (1) clinically relevant abnormalities unrelated to study medication, which was required to be between 80 and 120%.
Cetirizine/pseudoephedrine in seasonal rhinitis Table 1. Patients enrolled and completing the study: Reasons for with- Patients’ evaluations: The primary efficacy measure was based on the scores for the five symptoms, as assessed by the patients, over the total treatment period. The highest score of any one of the five symptoms, i.e. the score of the most severe symptom, was calculated each day for each patient, and this was called the “maximal symptom score.” The percentage of days with a maxi- mal score of 0 or 1, called “comfortable” days, was computed from the second day of treatment to the day before the last visit.
This primary outcome measure was selected since in our opin- ion it provides the most clinically relevant global measure of effective treatment of rhinitis, i.e. when symptoms do not dis- The Kruskal-Wallis test was used to compare the distribution of this variable between study groups, with a significance level of 5%. Comparisons of each of cetirizine and pseudoephedrine with the combination were performed using the Wilcoxon rank sum test, with a significance level of 3%.
Secondary efficacy variables were the mean 5-symptom score, Table 2. Patients’ characteristics at baseline.
the mean 4-symptom score (excluding nasal congestion) and individual mean symptom scores, over the whole treatment period. Global comparisons were performed on the variable using one-way analysis of variance, and two-by-two compari- sons were performed using Student’s t test.
Investigators’ evaluations: The severity of rhinitis at each visit was assessed by selecting the highest score of the five symp- toms. They were compared at each visit using the Cochran- Mantel-Haenszel (CMH) test stratified according to baseline (highest score at visit 1). Investigators’ global evaluations at the end of the study were also compared using the CMH test.
Safety: The number of patients in each treatment group with none, one, two, three or more adverse events was compared positive allergy tests* (% patients): Data from all patients receiving treatment were analysed on an intention-to-treat basis. Analyses were performed using SAS software, Versions 6.07 and 6.09 for VMS.
Of 687 patients with pollen-associated allergic rhinitis random- ized in the study by 43 investigators, 231 were randomized to severity of rhinitis (mean scores from patient diaries): cetirizine, 226 to pseudoephedrine and 230 to combination treatment with cetirizine and pseudoephedrine (Table 1). Three patients in each group did not return their daily record cards. A total of 616 patients (89.7%) evenly distributed between the three treatment groups completed the study. The reasons for withdrawal in 71 patients were lack of efficacy (30 patients); adverse events (22 patients); and other reasons unrelated to study drugs, mostly protocol deviations (19 patients; Table 1).
*: not all allergens were tested in every patient; **: excluding blocked The three groups were closely comparable in baseline characte- ristics: age, sex, body weight, allergies, duration of rhinitis, and severity of symptoms (Table 2). Since all patients had to have at Average compliance with treatment was estimated at 97-99%. The least one symptom of moderate severity to be eligible, there numbers and types of concomitant therapies prescribed during the were no “comfortable days” at baseline. As requested, nasal study were also similar in the various groups and consisted chiefly obstruction was of moderate to severe degree and a prominent of anti-asthmatics (28-32 in each group), topical nasal preparations symptom with mean scores of 2.2-2.3 across the three groups (13-15 in each group), ophthalmic preparations (9-15 in each group) and maintenance desensitization (11-13 in each group).
Five symptoms: At baseline, all patients had moderate to severe symptoms and mean scores were comparable (Table 2). During the 2-week treatment period, the proportion of “comfortable” days (symptoms absent or mild at the most) was significantly (p< 0.001) greater with the combination than with either cetiri- zine or pseudoephedrine alone; the median values were 53.3%, 30.8% and 33.3%, respectively, and the mean values 50.5%, Figure 3. Global evaluation of treatment by investigators (CET: cetiri- Figure 1. Percentage of “comfortable” days (no or only mild symp- zine; PSE: pseudoephedrine; COM: combination).
toms); •: median; ×: mean; bars represent the first and third quartile;CET: cetirizine; PSE: pseudoephedrine; COM: combination.
39.8% and 37.2%, respectively (Figure 1). The same conclusion Table 3. Mean scores over total treatment period for five symptoms, four was reached for the mean 5-symptom scores which were 0.85, symptoms and individual symptoms (daily record cards).
1.03 and 1.14, respectively (Table 3).
Four symptoms: The mean score of the four symptoms (sneez- ing, rhinorrhoea, nasal and ocular pruritus) over the total treat- ment period was significantly (p<0.001) lower for the combina- tion (0.77) than for cetirizine (0.93) or pseudoephedrine (1.12) Individual symptoms: Baseline scores for all symptoms were similar in the three groups (Table 2). The pattern and time- course of improvement in mean scores is shown in Figure 2 (graphs 1-5). Improvement was significantly (p≤0.01) greaterwith combination treatment than with cetirizine for all symp- toms (except itchy eyes) and greater than pseudoephedrine alo- ne for all symptoms, except nasal congestion (Table 3).
Maximal symptom scores: The mean maximal score of the five symptoms as assessed by investigators was calculated for each visit. Baseline values were similar in the three groups (2.77- comparisons versus combination: **0.001<p≤0.01;***p < 0.001 2.78). Investigators judged combination therapy (mean maxi- Cetirizine/pseudoephedrine in seasonal rhinitis Figure 2. Graphs 1-5: Mean individual symptom scores rated daily by patients. Graph 6: Mean maximal symptom scores rated by investigators at thevisits (bars represent two standard errors).
mum score: 1.53) to be significantly more effective than either mouth (pseudoephedrine 4.4%; combination 7.4%). Minor labo- cetirizine or pseudoephedrine (mean maximum score: 1.76 and ratory test abnormalities in 7 patients were not considered 1.82, respectively; p<0.01) as sole therapy after the first week clinically relevant. Mean heart rate increased by 2.2 and 3.2 and also after the second week (combination: 1.29; cetirizine: beats/min, between the first and the last visit, respectively in the 1.63, [p<0.001]; pseudoephedrine: 1.53 [p=0.031]). The pattern pseudoephedrine and combination groups.
of response for the mean maximal score of the five symptoms is apparent in Figure 2 (graph 6). Nasal obstruction scores with combination treatment were significantly lower than after cetiri- These results in a large group of patients with pollen-associated zine (p<0.001) but not pseudoephedrine, after both one and two allergic rhinitis of moderate to severe degree show that combi- ned treatment with cetirizine and pseudoephedrine provides Global evaluation of treatment: Analysis of investigators’ global greater symptom relief than either agent alone. The combina- evaluations of treatment also confirmed that combination tion led to more improvement than pseudoephedrine alone in therapy was significantly more effective than either cetirizine “histamine-induced” symptoms of sneezing, rhinorrhoea, nasal (p=0.001) or pseudoephedrine (p=0.007) taken alone (Figure 3).
and ocular pruritus. Compared with cetirizine, the combination Good to excellent results were reported by 69% of the patients was, as anticipated, more effective in relieving nasal congestion, in the combination group, in 56% of the patients in the cetirizi- but also the other three nasal symptoms (sneezing, rhinorrhoea ne group, and in 58% in the pseudoephedrine group.
and nasal pruritus). A likely explanation for this finding is a “carry-over” effect due to the good relief from the nasal conges- tion on the evaluation of the other nasal symptoms.
Adverse events (Table 4), whether or not considered drug- We defined the primary criterion of efficacy as the overall effect related, were reported by 54 patients (23.4%) taking cetirizine, of treatment over the 2-week study period and expressed this as 68 patients (30.1%) with pseudoephedrine, and 68 patients the percentage of “comfortable days”, i.e. days when patients (29.6%) with combination treatment (not significant). There were without symptoms, either moderate or severe in intensity.
were no serious adverse events. Adverse events were infre- We have previously explained why we believe this analysis is to quently considered severe and led to withdrawal from the study be preferred (Masi et al., 1993; Jobst et al., 1994) to a more con- in 6 patients (2.6%) on cetirizine, 7 patients (3.1%) on pseudo- ventional analysis of mean (or total) symptom scores. This ana- ephedrine, and 9 patients (3.9%) on combination treatment.
lysis is more demanding since it is driven by the least responsive symptom, but in the present instance it helped in separating the effects of the three treatments. However, we also analysed the mean scores to confirm our findings and again found the com- bination to be more effective than either of its components.
The results of investigators’ evaluations, made at review visits after one and two weeks, also confirmed the greater efficacy of combination treatment. For this analysis we used again the maximal scores, i.e. the scores of the most severe symptom, to characterize disease severity. Global evaluations by investiga- tors at the end of the study also favoured combination treat- The incidence of adverse events was in line with the known safety profiles of the agents and there were no unexpected or serious adverse events. The incidence of severe adverse events was twice as high with combination treatment compared to ceti- number of patients (%) with most frequent adverse events: rizine alone. This is the price which must be paid for increased efficacy, as suggested by the drop-out rates: more withdrawals because of adverse events with combination treatment and, by contrast, more due to lack of efficiency with the single agents.
The results of this trial are consistent with those of comparable combination products (Backhouse et al., 1990; Bronsky et al., 1995; Dockhorn et al., 1996) and of a previous study in which *possibly drug-related adverse events: cetirizine: 2; pseudoephedrine: cetirizine and pseudo-ephedrine alone were compared with the combination in patients with perennial allergic rhinitis (Bertrand et al., 1996). We conclude that a combination of ceti- Adverse events reported most frequently were somnolence rizine (5 mg) and pseudoephedrine retard (120 mg), both given (6.1%) and headache (4.3%) with cetirizine, and in those on twice daily over a 2-week period, is a well tolerated and effective pseudoephedrine and combination treatment, headache (pseu- treatment for the symptoms of seasonal allergic rhinitis, par- doephedrine 7.1%; combination 3.9%), sleep disorders, mostlyinsomnia (pseudoephedrine 11.1%; combination 6.9%) and dry ticularly when nasal congestion is a prominent symptom.
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Germany. They are indebted to J.L. Marchal for supplementary 8. Jobst S, Van den Wijngaart W, Schubert A, Van de Venne H (1994) statistical analyses, and to C. Arendt for the medical monitoring Assessment of the efficacy and safety of three dose levels of cetiri- zine given once daily in children with perennial allergic rhinitis.
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