EurJ Clin Pharmacol (1991) 41:321-324

of (~[~(~@~

EuropeanJournal

@ Springer-Verlag 1991

Effects of terfenadine and pseudoephedrine, alone and in combination in a nasal provocation test and in perennial rhinitis S. H e n a u e r 2, M. Seppey 1, C. H u g u e n o t 1, and A. P6coud 1 Division d'immunotogie et d'allergie ~ Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne and 2 Merrell Dow Research Institute, Winnersh, Switzerland and UK Received: May 29, 1990/August 24, 1990

Summary. The effects of terfenadine and pseudoephedrine, alone and in combination, have been assessed in a nasal provocation test and in perennial rhinitis. In a double-blind, placebo-controlled cross-over nasal provocation test, twelve men allergic to grass pollen were treated with two daily doses of placebo, terfenadine 60 mg, pseudoephedrine 120 mg, or the combination of the two, for 2 days preceding each test. The allergic reaction threshold, based on rhinorrhoea, sneezing and nasal inspiratory p e a k flow rate, was raised significantly both by terfenadine and pseudoephedrine, and their effects appeared additive (repeated measures analysis of variance). In a double-blind, randomized clinical study of perennial rhinitis two parallel groups, the efficacy and tolerability of terfenadine and terfenadine-pseudoephedrine were c o m p a r e d in 50 patients. Symptoms and signs in both groups were improved after 14 days of treatment. Differences between groups showed a trend in favour of terfenadine-pseudoephedrine, for swelling of the nasal mucosa (rhinoscopy) they were statistically significant. Both medications were well tolerated overall, although adverse events and reactions were more frequent in the terfenadine-pseudoepherine group. In conclusion, terfenadine-pseudoephedrine and its constituents taken alone were effective. The combination p e r f o r m e d better, but adverse events were somewhat m o r e frequent with the combination than with terfenadine alone. Key words: Terfenadine, Pseudoephedrine, Perennial rhinitis; nasal provocation test, rhinometry, adverse events

Terfenadine is a widely used antihistamine in the treatment of allergic rhinitis. It helps to relieve rhinorrhoea, sneezing, nasal pruritus and conjunctivitis [1]. Pseudoephedrine is a nasal decongestant that shrinks the swollen turbinate, mucosa, which is mainly effective against nasal congestion [2]. Since the effects of the two compounds c o m p l e m e n t each other, it seemed rational to combine them.

Combinations of antihistamines and pseudoephedrine are quite widely used and are generally safe and effective [3, 4], although this view is not universally shared [5, 6]. They usually contain an antihistamine which is sedative, whereas the combination tested in these studies contained terfenadine, a non-sedative antihistamine [7, 8]. The results are reported of two studies carried out to assess the effects of a terfenadine-pseudoephedrine combination tablet, namely a nasal provocation test and a clinical study in perennial rhinitis. Subjects and methods Nasal provocation test Participants. One woman and 12 men with a history of hay fever documented by positive skin prick tests and RASTfor grass pollen (Pharmalgen and Phadezym, respectively, Pharmacia, Uppsala, Sweden) participated. Their mean age was 30 y (SD 9 y), mean weight 80 kg (SD 31 kg), and they were all symptom free prior to testing. Perennial rhinitis, concomitant diseases and treatments that might have influenced the outcome were excluded prior to admission. Study design and assessments. A four-period cross-over study was done, in which each subject received four treatments (see below) in a different order, with at least one week in between. The allocation of treatment sequences was randomised by means of a computer generated random code. The nasal provocation test is described in detail elsewhere [9]. In brief, 0.2 ml vehicle (0.3 mg/ml human albumin, 4 mg/ml phenol) was nebulized into each nostril (De Vilbis vaporiser), followed by increasing allergen concentrations at 10 rain-intervals, from 100 to 100'000 BU/ml (standardised extract Pharmalgen, Pharmacia). The "allergic reaction threshold" was reached when two of the following criteria were met within the 10 rain following each provocation: rhinorrhea > 0.5 g (measured by weighing paper handkerchiefs); sneezing _>4 times; nasal inspiratory peak flow rate decreased by > 40% (compared to response after vehicle administration). Treatment. The following four identical looking medications were used: 1) terfenadine-pseudoephedrine (60 mg terfenadine rapid release and 120mg pseudoephedrine controlled release), 2)terfenadine (60 mg rapid release), 3) pseudoephedrine (120 mg controlled release), and 4) placebo. The patients received 5 tablets and were instructed to take one each morning and evening, starting two days before the test (last tablet to be taken 2 h before the test).

322

S. Henauer et al.: Terfenadine after Nasal Challenge and in perennial rhinitis

Table 1. Demographics and medical history of the participants in the perennial rhinitis study Terfenadinepseudoephedrine n = 25

Terfenadine n = 25

11 14

10 15

Sex

male female

Bodyweight

[mean(SD) kg] 65 (12)

Smoker

yes

11

Age

[mean(SD) y]

35

Phadiatop (modified

positive negative

4 21

8 17

Rhinitis since 1-5 y >5y unknown

12 11 2

12 13 0

Previously yes responded to no antihistamines unknown

3 l 21

5 1 19

63 (10) 5

(9)

27

(8)

pothesis procedure (SYSTAT software, Evanston, USA), using a repeated measures model with two trial factors (terfenadine, pseudoephedrine), each with two levels (0 mg and 60 mg, or 120 rag, respectively). Since each patient received the treatments randomly, and in a different order, period effects were not taken into account. In the perennial rhinitis study, the overall relief rating was the main endpoint for the efficacy evaluation. Secondary endpoints were the rhinoscopy assessments and the symptom ratings by the physician. The primary endpoint for tolerability was the frequency of patients with adverse events and reactions. Statistical tests and two-sided probabilities are reported in the 'Results' section. "Test" software by IDV (Gauting, FRG) was used for all tests.

Ethics

RAST) Both studies were carried out in accordance with the Declaration of Helsinki. Patients were informed about the nature, objectives, benefits and risks of the study, and verbal consent was obtained. The protocols were approved by the Ethical Review Committee of the local hospital.

Results

Nasal provocation study Perennial rhinitis study Participants. Fifty patients suffering from perennial rhinitis participated. Their demographics and medical history are summarised in Table 1. Allergy to domestic animals and relevant concomitant diseases and therapies were excluded prior to admission. All patients rated at least 1 of the 6 rhinitis symptoms on the diary card as 'troublesome'. Six patients suffered from a common cold during the study (terfenadine-pseudoephedrine N = 1, terfenadine N = 5).

Study design and assessments. Double-blind comparison of two parallel groups. Patients were randomly allocated to 1 of the 2 treatments by a computer generated random code in Blocks of 10. The severity of the following symptoms was rated weekly by the investigator using a visual analogue scale (0 mm = absent, 100 mm = severe): nasal congestion, sneezing, rhinorrhaea, itchy nose and/or throat, itchy eyes, watery eyes, red eyes. The patients rated the same symptoms daily on a 4-point rating scale (0 no symptoms, 1 symptoms hardly troublesome, 2 symptoms troublesome, 3 symptoms very toublesome). Tolerability was rated on Days 7 and 14 and included a check-list of potential adverse reactions (drowsiness, nervousness, headache, isomnia, dry mouth, nausea, palpitation). Swelling and hyperaemia of the nasal mucosa, nasal secretion and nasal obstruction were assessed by rhinoscopy on Days 0, 7 and 14; 4-point rating scale: 0 = none to 3 = severe. Olfaction was assessed on Days 0 and 14 using three different concentrations of camphor, ammonia, mint, vanilla, cinnamon, lavender and anise (concentrated solution, and 100- and 10-fold dilutions). Detection and identification of the substances were tested at random order, always starting with the lowest concentration. Blood pressure was measured on Days 0, 7 and 14 (sitting, after 5 rain rest). ECG was recorded on Days 0 and 14. Compliance was rated on Days 7 and 14, and acceptability onDay 14.

Allergic threshold. T h e t h r e s h o l d s in the 12 p a t i e n t s w h o c o m p l e t e d the s t u d y are shown in Fig. 1. T h e g e o m e t r i c m e a n s w e r e 196 B U / m l for p l a c e b o , 757 B U / m l for p s e u d o e p h e d r i n e , 1 7 9 0 B U / m l for t e r f e n a d i n e a n d 3860 B U / m l for t e r f e n a d i n e - p s e u d o e p h e d r i n e . T h e effects of b o t h t e r f e n a d i n e a n d p s e u d o e p h e d r i n e w e r e significant ( F = 5 . 5 0 0 , P = 0 . 0 3 9 a n d F = 6 . 6 1 1 , P =0.026, r e s p e c t i v e l y ) , a n d t h e r e was no i n t e r a c t i o n ( F = 1.007, P = 0.327), i n d i c a t i n g that t h e r e was n e i t h e r a n t a g o n i s m n o r s y n e r g i s m b e t w e e n t h e effects. A n a d d i t i o n a l c o m p a r i s o n of t e r f e n a d i n e a n d terf e n a d i n e - p s e u d o e p h e d r i n e at t h e h i g h e s t c o m m o n allergen c o n c e n t r a t i o n s h o w e d t h a t the m e a n n a s a l i n s p i r a t o r y p e a k flow r a t e was r e d u c e d to 46.3% ( S D 29.9) a n d 55.5% ( S D 30.6), respectively. T h e m e a n a m o u n t of s e c r e t i o n w e i g h e d 1.2 g ( S D 1.0) a n d 0.8 g ( S D 0.7), respectively.

Adverse events. O n e p a t i e n t w i t h d r e w f r o m the study a f t e r two test p e r i o d s ( t e r f e n a d i n e a n d t e r f e n a d i n e - p s e u d o e p h e d r i n e ) b e c a u s e of i r r i t a t i o n a n d dryness in the p h a r y n x o n o n e occasion, a n d p e r s i s t e n t itch in n o s e a n d e y e s on t h e s e c o n d occasion. T h e allergic t h r e s h o l d c o u l d n o t

g

100000 (BU/ml) 10000

E

8 c o o

Treatments. 25 patients received terfenadine-pseudoephedrine and

g

25 terfenadine. Both medications looked identical (see Nasal Provocation Test). Most patients appeared to have taken their medication regularly, i. e. one tablet each morning and evening for 14 days.

<

1000

100

10

Statistical analysis The primary endpoint for analysis in the nasal provocation test was the "allergic reaction threshold". After logarithmic transformation, the data were analysed by means of a multivariate general linear hy-

Placebo

P

-i

T+P

Fig. 1. Allergic thresholds (log geometric mean and SO) assessed by the nasal allergen provocation test after each of the four treatments terfenadine-pseudoephedrine (T+P), terfenadine (T), pseudoephedrine (P) and placebo. Four-way cross-over study in 12 patients

323

S. Henauer et al.: Terfenadine after Nasal Challenge and in perennial rhinitis Table 2. Symptom relief rated by the investigator on Day 14 Relief

complete (no symptoms present) marked (symptoms vastly improveds carcely troublesome) moderate (symptoms noticeably improved, may be troublesome) slight (symptoms minimally improved) none (symptoms unchanged) worse (symptoms worse than at entry visit) rating not available

Terfendinepseudoephedrine n = 25

Terfenadine n -- 25

2

0

8

5

5

10

4

7

4

1

0 2

0 2

be determined in either of those two tests. A m o n g the 13 patients, 7 reported adverse reactions, which were considered 'possibly or probably related to the drug treatment'. The adverse events were similarly distributed between treatments, and included dry mouth, mild asthenia, nervousness, somnolence, earlier sleep, hunger, irritation, dryness in the pharynx, insomnia, rhinorrhoea, headache, rhinitis, sneezing and thoracic oppression.

Perennial rhinitis study Symptom relief. Complete and marked relief was observed more frequently in the terfenadine-pseudoephedrine group (Table 2), but differences between the treatment groups were not significant (Mantel-Haenszel test, P = 0.27 on Day 7, and P = 0.69 on Day 14). Stratification according to the degree of nasal congestion on admission (two strata: scores 0-1 and scores 2-3) increased the overall P-values. All seven symptoms were improved according to both the investigator and the patient ratings. The results appeared to favour terfenadine-pseudoephedrine, but the differences between groups were statistically not significant (Investigator ratings, Fig. 2).

fenadine-pseudoephedrine), conjunctivitis and dry skin (terfenadine-pseudoephedrine), and dry skin (terfenadine). Adverse events were more frequent in the terfenadinepseudoephedrine group (20/25 vs 9/25; Fisher test P = 0.004), the most frequent being insomnia (13 vs 3), dry mouth (11 vs 2) and headache (8 vs 4). Severity in most cases was rated as moderate or severe, and events were considered to be related to the study drug in all but one case, i. e. they were adverse reactions. Except for three patients who withdrew, no action was required and the patients recovered spontaneously. Mean blood pressure ( m m H g ) and heart rate (beats min- 1), and mean PQ-, ORS- and QT-intervals (ms) in the ECGs of the two treatment groups hardly changed during the study, as shown by comparison of the groups on Days 0 and 14. In the terfenadine-pseudoephedrine group mean blood pressure (SD) changed from 122(6)/81(6) to 120(8)/79(4), and in the terfenadine group from 117(5)/79(4) to 117(6)/79(5)mmHg. Heart rate (ECG) changed from 67(12) to 72(15) and from 69(13) to 67(11) b.p.m., respectively, and Q T from 37(3) to 35(3) and 38(10) to 35(2) msec, respectively.

Acceptability. 15 patients in the terfenadine-pseudoephedrine group (65%) and 18 of the terfenadine group (78%) indicated that they would take the medication again if it were available.

Nasal congestion Sneezing Rhinorrhea Itchy nose Itchy eyes Watery eyes Red eyes

m

/

m N m m m m m m m m mmm

I -30

-20

-10

0

10

20

30

Difference between treatment groups (mm) Fig.2. Symptom severity ratings by the investigator (100 mm visual analogue scale) in patients who received either terfenadine-pseudoephedrine (n = 25) or terfenadine (M = 25) for 14 days. Mean difference for each symptom between treatment groups and 95% confidence intervals in regard to changes in severity from Days 0 to 14

25 Frequency (severe or moderate swelling)

Rhinoscopy. All four variables indicated improvement in favour of terfenadine-pseudoephedrine; one, swelling of the mucosa, is presented in Fig. 3. Differences between treatment groups were significant for swelling of the nasal mucosa (Mann-Whitney-U-test, P = 0.01), but not for obstruction (P = 0.24), secretion (P = 0.92) or hyperaemia (P =0.66).

Sense of smell Visual inspection of the results indicated only minimal improvement in the ability to smell.

Tolerability. The medications were well tolerated (overall rating), with the exception of three patients who withdrew because of adverse events. Those events included nervousness, insomnia, headache, dry mouth and nausea (ter-

20 15 10 Day 0 Day 7 Day 14

5 0

Terfenadinepseudoephedrine

Terfenadine

Fig. 3. Swelling of the nasal mucosa (rhinoscopy) before, and after 7 and 14 days of treatment with terfenadine-pseudoephedrine or terfenadine. Frequencies of moderate or severe ratings are presented. n = 25 in each group on Day 0, n = 24 on Day 7 and n = 23 on Day 14.

324

S. Henauer et al.: Terfenadine after Nasal Challenge and in perennial rhinitis

Discussion The results were not surprising in view of the difficulty of showing what were expected to be small differences between two or more effective compounds. Combinations of antihistamines and pseudoephedrine are no exception. Although they are widely used and are considered effective [3, 10-12], there are also studies that have failed to demonstrate the superiority of such combinations over their single ingredients [13-15]. Several of the positive studies may have had a positive outcome by chance, if considered that significance levels were not adjusted for multiple testing [16]. Terfenadine and pseudoephedrine are both known to be effective in the treatment of allergic rhinitis [10, 17, 18], and this was confirmed in the two studies here. The combination of the two proved somewhat better, but the difference was small. Of course, differences m a y be small because of similar efficacy of the tested drugs, but other factors may also be involved, e.g. study design and patients. It is unlikely that they would have influenced the outcome in an unfavourable way. The design of the perennial rhinitis study has proved successful in other investigations, and the two treatment groups were fairly similar with respect to prognostic variables. The nasal provocation test was sufficiently sensitive to capture the effects of the single ingredients. A subgroup of perennial rhinitis patients was examined, who rated nasal congestion as troublesome, expecting better relief with terfenadine-pseudoephedrine than with terfenadine alone. This was not supported by the results. Terfenadine performed better than pseudoephedrine in the nasal provocation test. This was unexpected, because the threshold is mainly determined by rhinorrhoea and obstruction, and therefore the decongestant pseudoephedrine should have p e r f o r m e d better than the antihistamine terfenadine. Adverse events were mild and infrequent in the nasal provocation test, but treatment lasted only two days. In contrast, a relatively high frequency of adverse events was observed in the perennial rhinitis study, even when compared with published results [19]. The discrepancy may be explained by the fact that a checklist of expected adverse reactions was used and this usually leads to higher reporting rates. It is m o r e important that observed adverse events were clearly m o r e frequent with terfenadine-pseudoephedrine than with terfenadine alone, and that the severity was often rated as ' m o d e r a t e ' or 'severe'. The latter m a y be offset by the overall tolerability rating and the acceptability assessment, both of which indicated that these events were not very disturbing. The observed adverse events appeared like typical pseudoephedrine side-effects, which are well known and have been investigated after sustained release formulations [20]. According to Stroh et al. [19], terfenadine-pseudoephedrine is tolerated as well as pseudoephedrine alone, and pseudoephedrine is generally regarded as safe [2, 21]. In conclusion, terfenadine-pseudoephedrine appeared more effective than either of its constituents alone, but it was less well tolerated than terfenadine alone. It should be

interesting to investigate other indications and to attempt further differentiation between the various effects.

References 1. Sorkin EM, Heel RC (1985) Terfenadine. A review of its pharmacodyn amic properties and therapeutic efficacy.Drugs 29:34-56 2. Food and Drug Administration (1985) Tentative final monograph for OTC antihistamine products. Fed Reg 50:2219-2241 3. Food and Drug Administration (1988) Proposed rules. Fed Reg 53:30522-30564 4. Morgan JP (1987) Over the counter availability of sympathomimetics. Br Med J 295:924 5. Whitehouse A (1987) Over the counter availability ofsympathomimetics. Br MedJ 294:1308 6. Whitehouse A (1987) Over the counter availability ofsympathomimetics. Br Med J 295:924 7. Nicholson AN, Stone BM (1986) Antihistamines: Impaired Performance and the Tendency to Sleep. Eur J Clin Pharmacol 30: 27-32 8. O'Hanlon JF (1988) Antihistamines and Driving Safety. Cuffs 42(4A): 10-13 9. Kolly M, Pecoud A (1986) Comparison of levocabastine, a new selective Hi-receptor antagonist, and disodium cromoglycate, in a nasal provocation test with allergen. Br J Clin Pharmacol 22: 389-394 10. Empey DW, Bye C, Hodder M, Hughes DTD (1975) A doubleblind crossover trial of pseudoephedrine and triprolidine, alone and in combination, for the treatment of allergic rhinitis. Ann Allergy 34:41-46 1l. Empey DW, Young GA, Letley E, John GC, Smith R McDonnell KA, Bagg LR, Hughes DTD (1980) Dose-response study of the nasal-decongestant and cardiovascular effects of pseudoephedrine. Br J Clin Pharmacol 9:351-358 12. Connell JT, Williams BO, Allen S, Cato A, Perkins JG (1982) A double-blind controlled evaluation of Actifed and its individual constituents in allergic rhinitis. J Int Med Res 10:341-347 13. Cohen BM (1975) Physiologic/clinical comparisons of a sustained-release decongestant combination, its components and placebo in patients with allergic rhinitis. J Asthma Res 13:7-13 14. Empey DW, Frosolono ME Hughes DT, Perkins JG (1984) Comparison of pseudoephedrine and triprolidine, alone and in combination in preventing nasal congestion in subjects with allergic rhinitis using nasal histamine challenge. Br J Clin Pharmacol 18: 86-89 15. Diamond L, Gerson K, Cato A, Peace K, Perkins J (1981) An evaluation of triprolidine and pseudoephedrine in the treatment of allergic rhinitis. Ann Allergy 47:87-91 16. Falliers CJ, Redding MA (1980) Controlled comparison of a new antihistamine-decongestant combination to its individual components. Ann Allergy 45:75-80 17. Backhouse CI, Brewster BS, Lockhart JDF, Maneksha S, Purvis CR, Valle-Jones JC (1982) Terfenadine in allergic rhinitis. A comparative trial of a new antihistamine versus chlorpheniramine and placebo. Practitioner 226:347-351 18. Boland N (1988) A double-blind study of astemizole and terfenadine in the treatment of perennial rhinitis. Ann Allergy 61 : 18-24 19. Stroh Jr. ER, Ayers OH, Bernstein IL, Kemp JP, Podleski WK, Prenner BM, Schoenwetter WF, Salzmann JK (1988) A comparative tolerance study of terfenadine-pseudoephedrine combination tablets and pseudoephedrine tablets in patients with allergic or vasomotor rhinitis. J Int Med Res 16:420427 20. Dickerson J, Perrier D, Mayersohn M, Bressler R (1987) Dose tolerance and pharmacokinetic studies of L ( + ) pseudoephedrine capsules in man. Eur J Clin Pharmaco114: 253-259 21. Porta M, Hershel J, Habankangas JAS (1986) Follow-up study of pseudoephedrine users. Ann Allergy 57:340-342 S. Henauer M. D. Marion MerrelI Europe AO, BahnhofstraBe 20 CH-8800 Thalwil, Switzerland