Comparative Trial of Two Dose Regimens of Terfenadine in Patients with Hay Fever

Transcription

1 J Int Med Res (1984) 12,333 Comparative Trial of Two Dose Regimens of Terfenadine in Patients with Hay Fever J C Murphy-O'Connor, LRCPI, LRCSI, R L Renton, MB, ChB, DIU, and D M Westlake, MB, BS, General Practitioners, Slough, Buckinghamshire, England Eighty patients with hay fever took part in a double-blind study to compare the efficacy of two doses of terfenadine, namely mg b.d., the standard recommended dose, and 1 mg b.d. Thirty-nine patients received mg b.d. and thirty-eight received 1 mg b.d., each given over 1 week. Symptoms were assessed at the start and end of treatment and were also recorded in diary cards. Over-all efficacy was determined by doctor and patient at the end of treatment. Onset of relief of symptoms after the first dose was recorded. The results showed no significant differences between the two treatments. Symptom reliefwas goodfor both (54%-63% experiencing good or complete relief) and the target symptoms of hay fever (i.e. those most commonly reported) were relieved particularly well. Average onset of symptom relief was 72 minutes for mg and 59 minutes for 1 mg. Side-effects werefew for both doses, only three patients in total reporting sedation. Introduction Terfenadine (Triludane") is a non-sedative antihistamine which has now been widely tested and found effective in a number of allergic conditions (Backhouse et al 1982, Cerio & Lessof 1984). Doses very much higher than the usually recommended therapeutic dose of mg b.d. have been widely used in volunteer studies and no CNS effect has been noted even when 2 mg is given as a single dose (Moser et al 1978). The present therapeutic dose was decided upon from the results of histamine weal studies which showed no difference in the degree of weal inhibition following doses of mg b.d. or following higher doses (Huther et al 1977). The appropriateness of this dose has been confirmed both by controlled clinical trials and -Merrell Dow Pharmaceuticals Ltd. by general clinical experience but anecdotal reports received from practising clinicians have suggested that some patients whose symptoms are not fully controlled by mg b.d. may respond better, and perhaps more quickly, to a higher dose. It was decided, therefore, to compare efficacy, incidence of adverse effects and onset of action of a higher dose (1 mg b.d.) with the standard dose regimen in a double-blind study. Methods Patients with hay fever, aged over 15 years, were admitted to this study carried out in a single general practice during the summer of All patients gave informed consent. The severity of seven main symptoms, i.e, nasal block, rhinorrhea, sneezing, itchy nose, watery eyes, itching eyes and red eyes, were graded on a simple numerical scale as follows:

2 334 o - symptom absent 1 - mild, symptom present but not troublesome 2 moderate, frequently troublesome but not interfering with activity or sleep 3 severe, interferes with daily activity or sleep. For admission to the trial at least one symptom needed to be graded 2 or 3. After initial assessment patients were randomly allocated to receive double-blind either mg b.d. or 1 mg b.d. for 1 week. Patients were given a diary card to fill in every day with instructions to record severity oftheir symptoms and any untoward effects. They were also asked to record the time taken for the first dose to begin to relieve symptoms. On return to the surgery 1 week later symptoms were re-assessed, side-effects were sought and an over-all conclusion on efficacy of the treatment was made by both patient and investigator. Statistical analysis of comparisons between the two groups were made using x 2 test. Results Eighty patients entered the study and there was one withdrawal from the high dose group for a chest infection and two patients did not return, one from each group. The characteristics of the two groups of patients were similar in terms of age, sex, previous response to antihistamines and previous sideeffects with antihistamines (see Table 1). The Journal ofinternational Medical Research Table 1 Characteristics of patients completing trial Dose mgb.d. 1mgb.d. Number of patients Sex Male % Female % Age Mean Range Previous antihistamine Response % good fair poor Drowsiness % The results of the assessments by doctor and patient are presented in Table 2. There is no significant difference in symptom response between the two treatment groups. Good or complete symptom relief was experienced by 55% of those receiving mg b.d, and by 62% on the higher dose. Total symptom scores were reduced by 59% ( mg b.d.) and 48% (1 mg b.d.). Analysis ofthe patients' diary cards during the week is presented in Figure 1. There is some variation in the response to treatment of the various symptoms but the three most commonly reported symptoms, sneezing, Table 2 Assessment of response by doctor and patient Dose mgb.d. 1 mg &.<1. Response % Doctor Patient Doctor Patient Complete Good Slight None N/S 2 6

3 J C Murphy-O'Connor, R L Renton and D M Westlake 335 l1li mg bd D 1mgbd DAY DAY SNEEZING NASAL BLOCK DAY DAY RUNNING NOSE ITCHING NOSE Fig 1 Mean percentage improvement ofsymptom scores as recorded in patient diary cards

4 336.mgbd The Journal ofinternational Medical Research c:=j 1 mg bd DAY RED EYES 6 7 DAY WATERY EVES 6 7 running nose and itching eyes respond to treatment better than the others. It may also be noted that most of the benefit occurs by the end of the first days treatment, with few important differences afterwards. The time to the onset of symptom relief was similar for both doses with most patients reporting relief of symptoms within 1 hour. Mean onset was 72 minutes for mg b.d. and 59 minutes for the higher dose. Side-effects reported were infrequent, although more were in high dose patients (Table 3). Drowsiness was noted in only three patients (4%). OAY 2 Fig 1 (continued) ITCHING EVES 6 7 Discussion The results of this study have confirmed that terfenadine at the usual recommended dose is effective for symptom relief in hay fever and gives a similar degree of control to that reported by these patients on their previous antihistamine therapy. There is no significant improvement of symptom response when the

5 J C Murphy-O'Connnor, R L Renton and D M Westlake 337 Table 3 Side-effects mgb.d. 1mgb.d. Drowsiness I 2 Dry mouth - 2 Headache I I Rash I I Wheezy chest - I Nausea - I dose is doubled, suggesting that the present dose is indeed the optimal one in the majority of patients. The question of whether patients who do not respond satisfactorily to mg b.d. may do so to a higher dose has not been tested and could be the subject of another trial. Whilst over-all efficacy has been satisfactory it is encouraging to observe that the greatest relief was obtained for the most commonly reported symptoms. A similar observation was made by Dugue et al (1982) who showed an advantage for terfenadine over dexchlorpheniramine in controlling these target symptoms. The time elapsed from taking the first dose to the onset of symptom relief confirms what might have been expected from a knowledge of terfenadine pharmacokinetics. Terfenadine is rapidly absorbed and reaches a peak plasma concentration after about 2 hours whilst inhibition of histamine weal is apparent after 1 hour and peaks after 4 hours (Garteiz et al 1982). The majority of our patients experienced relief within 1 hour (55% with mg, 66% with 1 mg) and most within 2 hours (84% and 86%, respectively). Rapid relief of the acute symptoms of hay fever is certainly a necessary property for an antihistamine. Once again, the lack of sedation experienced with terfenadine has been confirmed even when the dose is doubled. The very low incidence in each group should be compared to the % incidence of drowsiness reported by these patients for when they had previously used other antihistamines (Table 1). Whilst historical data of this sort should be used cautiously for purposes of comparison, the difference with terfenadine is clearly clinically and statistically significant. We conclude that increasing the dose of terfenadine in patients with hay fever does not appear over all to confer any greater degree of therapeutic efficacy. The onset of antihistamine effect may be quicker with the higher dose but there is no difference in the incidence of adverse effects. Acknowledgements We are grateful to Dr A Barr and his staff of the Oxford Regional Health Authority for carrying out the statistical analyses, and to Dr J D F Lockhart of Merrell Dow Research Institute for the supply of tablets. REFERENCES Backhouse C I, Brewster B S, Lockhart J D F, Maneksha S, Purvis C R &Valle-Jones J C (1982) Terfenadine in allergic rhinitis. A comparative trial of a new antihistamine versus chlorpheniramine and placebo. Practitioner 226, 347 Cerio R & Lessor M H (1984) Treatment of chronic idiopathic urticaria with terfenadine. Clinical Allergy 14, 139 Dugue P, Birnbaum J, Poisson A & Charpin J (1982) Clinical studies with terfenadine in seasonal allergic rhinitis in France. Arzneimittel Forschung 32, 16 Garteiz D A, Hook R H, Walker B J & OkerhoIm R A (1982) Pharmacokinetics and biotransformation studies ofterfenadine in man. Arzneimittel Forschung 32, 1185 Huther K J, Renftle B, Barraud N, Burke J T & Koch WeserJ (1977) Inhibitory activity of terfenadine on histamineinduced skin weals in man. European Journal ofclinical Pharmacology 12, 195 Moser L, Huther K J, Koch-Weser J & Lundt P V (1978) Effects of terfenadine and diphenhydramine alone or in combination with diazepam or alcohol on psychomotor performance and subjective feelings. European Journal ofclinical Pharmacology 14,417