Terfenadine. An updated review of its pharmacological properties and therapeutic efficacy.

Drug Evaluation

Drugs 39 (4): 552-574, 1990 00 12-6667/90/0004-0552/$ 11.50/0 © ADIS Press Limited

All rights reserved. DREND2 648a

Terfenadine

An Updated Review of its Pharmacological Properties and Therapeutic Efficacy Donna McTavish, Karen L. Goa and Al ary Ferrill ADIS Drug Informat ion Services, Auckland, New Zealand, and College of Phar macy, University of Illinois at Chicago, Chica go, Illinois, USA

Various sections of the manuscrip t reviewed by: M . Akagi, Departmen t of Pharm acology, O kayama University, Okaya ma, Jap an; G. Bruttmann, G renoble, Fran ce; A. Gutkowski, St Mary' s Hosp ital, Mon treal, Canada; F. Horak, Vienna Hosp ital, Vienna, Aust ria; J.P. Kemp, Allergy & Asthma Med ical Group and Research Center, San Diego, Californ ia, USA; S. Makino, Departm ent of Medicin e & Cli nical Immunology, Dokkyo Unive rsity Schoo l of Med icine, T ochigi, Japan; E. Meltzer, Allergy & Asthm a Med ical G roup and Resear ch Center, San Diego, California , USA; A. Taytard, Department of Comm unity Medicine, St Th om as' Hosp ital , London, England; J.S. Turner, Emory University School of Med icine, Division of Otol aryngology, Atlanta , Georgia, USA; R. Wood-Baker, Facult y of Medici ne, Unive rsity of Sou thampton , Southampton Gen eral Hosp ital, Southamp ton , England.

Contents

Summary 1. Overview of Pharm acological Propert ies _ 1.1 Antihistaminic Activity 1.2 Antiallergic Activity 1.3 Psychom otor Performan ce, Reactivity and Sedation Studies 1.4 Pharmacokinetic Properties 1.4.1 Healthy Volunteers 1.4.2 Childre n with Allergic Rhinitis 2. Therapeutic Tr ials 2. 1 Seasonal Allergic Rhinitis 2.1.1 Noncomparative and Placebo-Controlled Studies 2.1.2 Dosage Regimen Stud ies 2.1.3 Comparisons with Other Histamine H I-Receptor Antagonists 2.1.4 Comparisons with Other Antiallergic Agents 2.2 Perennial Allergic Rhinitis 2.3 Allergic Dermatological Disorders 2.4 Bronchial Asthma 2.5 Common Cold 3. Adverse Effects 4. Dosage and Administration 5. Place of Terfenadine in Therapy

553 555 555 556 557 559 559 560 560 561 561 561 561 563 565 565 567 567 569 569 570

Terfenadine: An Updated Review

553

Summary Synopsis

Terfenadine is a selective histamine HI-receptor antagonist which. in pharmacodynamic studies. is devoid of central nervous system depressant activity. In clinical studies terfenadine is well tolerated and at a dose of 60mg administered twice daily the drug provides effective relief of symptoms in patients with allergic rhinitis (seasonal and perennial), allergic dermatological conditions (particularly chronic urticaria). and other histamine-mediated disorders. Terfenadine is superior to placebo. has a more rapid onset of action than astemizole and is as effective as most other histamine HI-receptor antagonists. in relieving rhinitis symptoms. In allergic rhinitis. terfenadine relieves ocular symptoms to a greater extent (but nasal symptoms to a lesser extent) than inhaled corticosteroids. Administration oforal terfenadine with inhaled sodium cromoglycate (cromolyn sodium) or an inhaled corticosteroid appears more effective than terfenadine alone. Despite the absence of eNS depressant activity in pharmacodynamic studies. sedation is the adverse effect most frequently associated with terfenadine treatment. However. it is important to realise that the incidence of this adverse effect is similar in terfenadine and placebo recipients. and is less frequent than with traditional histamine HI-receptor antagonists. In conclusion. terfenadine is a clinically effective antihistamine which has an improved adverse effect profile compared with classic histamine HI-receptor antagonists. Like other nonsedating antihistamines. it can be considered as a first-line agent in the treatment of allergic rhinitis and chronic urticaria. With additional clinical experience. the drug could find a similar role in other disorders in which a histamine HI-receptor antagonist is indicated.

Overview of Pharmacological

Terfenadine is a histamine H I-receptor antagonist which is selective for peripheral receptors in vivo and is active in several animal tests of antihistaminic activity. It has no significant affinity for histamine H2-receptors, or a- or p-adrenergic receptors, and has little or no antiserotoninergic, anticholinergic, and a- or p-adrenergic activity. In healthy volunteers, and in patients with allergic rhinitis or atopic asthma, a single dose ofterfenadine 60mg suppressed the weal and flare response to intradermally injected histamine for at least 12 hours, with a peak effect seen after about 3 hours. Terfenadine inhibited histamine-induced bronchoconstriction in asthmatic patients and increased FEYI by about 10% over a dose range of 60 to 180mg. Antiallergic activity demonstrated in animal models has been confirmed in atopic asthmatic patients. Terfenadine inhibited bronchoconstriction induced by inhaled allergen, nebulised distilled water or exercise, reduced the response to nasal allergen provocation, and inhibited the weal response to skin prick tests with allergen. Terfenadine does not impair psychomotor performance or reactivity and in doses up to 600 mg/day causes no more sedation than placebo. Like loratadine and acrivastine, terfenadine does not potentiate the central depressant effects of alcohol or diazepam. Terfenadine is rapidly absorbed after single-dose administration, with a mean peak plasma concentration of 1.5 ItgfL occurring about I hour after a 60mg oral dose. The drug is extensively metabolised following oral administration. After single and multiple doses of up to 240 mg/day, peak plasma concentrations of intact terfenadine are generally less than 10 ItgfL. However, the major metabolite (metabolite I) which retains antihistaminic activity reaches peak levels 2 to 3 hours after a single terfenadine dose in healthy adult volunteers and in children with allergic rhinitis and is detectable within 30 minutes of initial administration. Metabolite I peak plasma levels and AUC values increase linearly with doses up to 180mg. The terminal elimination half-life of metabolite I is approximately 17 hours. Plasma concentrations of metabolite I are not significantlyaffected by food or increasing age. Peak plasma concentrations of metabolite I appear to precede maximum antihistaminic activity by I to 3 hours. Animal studies have shown that after administration of 14C-terfenadine, radioactivity

Properties

554

Drugs 39 (4) 1990

levels are highest in lung and liver tissue and lowest in brain tissue. Elimination of 14C_ terfenadine is via urine (40% of an oral dose) and faeces (60%). Therapeutic Trials

The efficacy ofterfenadine has been evaluated in patients with allergic rhinitis (mainly seasonal), allergic dermatological disorders, bronchial asthma and the common cold. Terfenadine 60mg administered twice daily provides significantly superior relief of seasonal allergic rhinitis symptoms compared with placebo. Symptom relief and onset of improvement are similar in patients treated with terfenadine 60mg twice daily or 120mg once daily. In double-blind studies, terfenadine 60mg twice daily was comparable to chlorpheniramine (chlorphenamine) 12 rug/day, loratadine 10 or 40 mg/day, and mequitazine 10 rng/day, and superior to clemastine 2 mg/day in improving rhinitis symptoms. Terfenadine is, however, less efficacious than dexchlorphen iramine 12 mg/day but is comparable to a dosage of 6 mg/day, Terfenadine provides more rapid relief of symptoms compared with astemizole but in most studies both drugs appeared comparable after 8 weeks of treatment. In a study of children with seasonal allergic rhinitis , terfenadine 60 rng/day and astemizole 2 rug/day provided similar relief of nasal and ocular symptoms; however, astemizole appeared superior based on patients' and investigators' global assessment after 4 or 8 weeks. Ocular symptoms of allergic rhinitis were reduced to a greater extent by oral terfenadine than by inhaled beclomethasone dipropionate or flunisolide, but inhaled corticosteroids tended to be more effective in relieving nasal symptoms. Coadministration of terfenadine and inhaled flunisolide enhanced the effect on nasal symptoms of either drug given alone, and similarly a combination ofterfenadine and inhaled sodium cromoglycate (cromolyn sodium) appears more effective than terfenadine alone. In patients with perennial allergic rhinitis, terfenadine 60mg twice daily is comparable to ketotifen Img twice daily, cetirizine 10 rug/day, loratadine 10 rug/day, and chlorpheniramine 8mg twice daily but was less effective than astemizole 10 mg/day in reducing the severity of most symptoms. Terfenadine 60mg twice daily produced marked or complete relief of pruritus, size and number of weals after I week in patients with chronic urticaria and was equally effective when administered as a single daily 120mg dose. Based on global assessment of efficacy, the drug was at least as effective as brompheniramine 24 mg/day, hydroxyzine 100 rng/day, cetirizine 10 rug/day, chlorpheniramine 12 mg/day or clemastine 2 rng/day, but appeared less effective than azatadine 2 mg/day and had a less rapid and persistent effect than astemizole 10 rug/day. Combined treatment with terfenadine and ranitidine, a histamine Hj-receptcr antagonist, produced greater relief of pruritus than terfenadine or ranitidine alone in patients with chronic idiopathic urticaria . Compared with placebo, terfenadine 240 or 540 mg/day had a slight but significantly superior effect on asthmatic symptoms and pulmonary function. Studies conducted in Japan show that terfenadine 120 or 240 rag/day is superior to ketotifen 2 mg/day in asthmatic patients, with no difference seen between the dosages of terfenadine after 4 weeks. The role of terfenadine in the treatment of the common cold is not well defined and further studies are needed to clarify the results reported to date.

Adverse Effects

Sedation is the most frequently reported adverse effect associated with terfenadine therapy. The incidence of sedation and related effects (12.6% in 965 patients treated with terfenadine) is, like the incidence associated with other new antihistamines such as astemizole, azatadine, and loratadine, comparable with the incidence in placebo recipients and almost half that seen in patients treated with older antihistamines (e.g. chlorpheniramine, clemastine or dexchlorphen iramine). Dry mouth, nose or throat have been reported in 2.6% of terfenadine-treated patients (vs 2.2% of placebo recipients and up to 4.6% of patients receiving other classical antihistamines) and the incidence of headache (up to

555


18%) was similar in terfenadine and placebo groups. Other adverse effects associated with terfenadine treatment are gastrointestinal complaints (6.5%), allergy symptoms (9.1%), skin disorders (1.2%), musculoskeletal disorders (1.3%), cardiovascular effects (1.3%)and genitour inary disorders (1.1%), all of which tended to occur in a similar percentage of patients administered placebo. Dosage and Administration

The recommended terfenadine dosage in adults is 60mg administered twice daily. Children aged 3 to 5 years should receive terfenadine 15mg twice daily as an oral suspension, and in those aged 6 to 12 years a dosage of 30 to 60mg twice daily, depending on bodyweight, is recommended. A daily dosage of up to 540mg has been used in asthmatic patients.

This update reappraises the use of terfenadine in patients with seasonal or perennial allergic rhinitis, chronic urticaria, and atopic asthma. An overview of the pharmacology of the drug is provided, with emphasis on clinical data. Readers are referred to the previous review in the Journal (Sorkin & Heel 1985) for a more detailed evaluation of the pharmacodynamic and pharmacokinetic properties of terfenadine.

Additionally, terfenadine has no significant anticholinergic activity, as evidenced by its lack of effect on airway responsiveness to inhaled methacholine in asthmatic patients (Patel 1987; Rafferty & Holgate 1987) and its failure to inhibit salivary secretion, heart rate and pupil diameter in healthy volunteers at normal therapeutic doses (Brion et al. 1988; Kulshrestha et al. 1978; Vargas et aI. 1989). 1.1 Antihistaminic Activity

1. Overview of Pharmacological Properties In vitro receptor binding studies have shown that terfenadine has a selective and specific affinity for peripheral and central histamine HI-receptors (Wiech & Martin 1982). The drug concentration producing 50% inhibition of 3H-mepyramine binding (ICso) was 0.2 /Lmol/L for ileal receptors and 0.3 /Lmol/L for brain receptors . Terfenadine has no significant affinity for histamine H2-receptors or a (-, a2- , or J3-adrenergic receptors (Kinsolving et al. 1973; Wiech & Martin 1982). Unlike older histamine H (-receptor antagonists such as chlorpheniramine (chlorphenamine), diphenhydramine, promethazine and triprolidine, terfenadine has no significant affinity for central histamine receptors in vivo (Rose et al. 1982). Terfenadine has no significant activity on the tryptamine antagonism test in animal studies (EDso > 80 mg/kg), indicating weak antiserotoninergic activity, and is devoid of a- or J3-adrenergic receptor antagonist properties (Cheng & Woodward 1982a,b; Niemegeers et al. 1982).

Following a single 60mg dose of terfenadine, maximum suppression (approaching 100%) of the weal response in healthy volunteers is evident after 4 hours (Hiither et aI. 1977) and persists for more than 12 hours (Van Landeghem et al. 1980). More recently, in healthy volunteers, a single oral terfenadine dose of 120mg significantly reduced the weal area and weal and flare area in response to intradermally injected histamine for up to 24 hours compared with placebo (Shall et al. 1988) and suppressed the weal response to a histamine skin prick test more rapidly than astemizole (2 hours vs 3 days), but for a shorter duration (I day vs 28 days) [Tyolahti & Lahti 1989]. Maximal effects of the 2 drugs were similar in this study. Multiple-dose studies have also demonstrated a significantly superior effect over placebo for oral terfenadine 60mg administered every 8 or 12 hours for 3 days (Hiither et al. 1977; Ryan et aI. 1988). In healthy volunteers, terfenadine 60mg twice daily was as effective as 120mg once daily with regard to weal inhibition after 3 days' administration (Pecoud et al. 1988;

Drugs 39 (4) 1990

556

80

Tertenadine Astemizole

Azatadine Mequitazine

Fig. 1. Inhibition of histamine-induced weal area compared with pretreatment values after 15 (0) or 30 (_) days' treat-

ment with terfenadine 120 rug/day, astemizole 10 mg/day, azatadine 2 mg/da y or mequitazine 10 mg/day in 32 patients with perennial allergic rhinitis (after Malet et al. 1989).

Ryan et al. 1988), while a 120mg dose administered twice daily appeared more effective than 120mg once daily or 60mg twice daily after 3 days (Ryan et al. 1988). No subsensitivity was seen in healthy volunteers treated with terfenadine 60mg twice daily for 56 days, as assessed by histamineinduced weal and flare responses every 7 days (Simons et al. 1988). Children with seasonal allergic rhinitis administered the histamine skin-test have shown a similar pattern of response to terfenadine as adult volunteers. Terfenadine 15 to 60mg given as an oral suspension suppressed the histamine-induced weal and flare response for up to 8 hours, with maximum suppression seen at 3 to 6 hours (Simons et al. 1987) and , at a dosage of 60 mg/day, blocked the response to histamine skin prick tests lO-fold compared with placebo (Kjellman & Andersson 1986). An evaluation of 4 antihistamines over a treatment period of 30 days showed similar inhibition of histamine-induced weal area with terfenadine 120 mg/day, astemizole 10 rug/day, azatadine 2 rug/day or mequitazine 10 mg/day (fig. I). In asthmatic patients, most of whom were atopic, oral terfenadine reduced the mean skin weal area in response to histamine skin prick tests, although to a somewhat lesser extent than in the healthy volunteers described above. Reductions

were 46% after a 60mg dose, 69% after a 120mg dose, and 84%after a 180mgdose (Rafferty & Holgate 1987). Inhibition of histamine-induced bronchoconstriction is further evidence of the antihistaminic effects of terfenadine in asthmatic patients. Mean histamine doses required to reduce FEV I by 20% (PC20) were 3.8 Ilg/L after pretreatment with a single oral terfenadine 60mg dose, 8.1 Ilg/L after a 120mg dose, 8.7 Ilg/L after a 180mg dose, and 0.6 Ilg/L after placebo (Rafferty & Holgate 1987). Terfenadine 180mg was significantly (p < 0.05) more effective than a 60mg dose in protecting against histamine-induced bronchoconstriction and, at all dose levels, terfenadine slightly but significantly (p ::;;: 0.05) increased FEVI by 9 to 10% compared with pretreatment values. In another study, the FEVI response to challenge with histamine at mean PC20 doses in atopic asthmatic patients was suppressed by 97% after pretreatment with a single oral terfenadine 180mg dose and by 93% after pretreatment with oral terfenadine 180mg plus flurbiprofen 100mg, a cyclo-oxygenase inhibitor (Phillips & Holgate 1989). 1.2 Antiallergic Activity Skin prick, and nasal and bronchial challenge studies in humans generally confirm the antiallergic activity of orally administered terfenadine apparent in standard animal models of allergy (Akagi et al. 1987; Kreutner et al. 1987). In atopic patients terfenadine 60mg administered twice daily for 7 days markedly inhibited the nasal response (sneezing and secretion) to nasal allergen provocation but had little effect on nasal airway obstruction as assessed by rhinomanometry (Rokenes et al. 1988). In contrast, a higher single dose of terfenadine 180mg 3 hours prior to bronchial allergen challenge in 9 atopic asthmatic patients inhibited bronchoconstriction by approximately 50%, with a maximal effect seen within 10 minutes of allergen challenge (Rafferty et al. 1987). A smaller but statistically significant attenuation of the bronchial response to histamine or antigen has been reported in asthmatic patients given terfen-


adine 60, 120 or 180mg 12 and 4 hours before challenge (Chan et al. 1986). Single terfenadine doses of 120, 180 or 240mg provided significant protection against bronchoconstriction induced by inhaled adenosine monophosphate, nebulised distilled water or exercise compared with placebo in adult asthmatic patients (Hopp et al. 1988; Patel 1984; Phillips & Holgate 1989; Rafferty et al. 1987; Townley et al. 1989; Wiebicke et al. 1988). When administered 3 hours before isocapnic hyperventilation in asthmatic patients, a single oral dose of terfenadine 120mg had no significant effect oil the mean maximal fall in FEY I (Wiebicke et al. 1988). Another group of investigators has demonstrated a significant protective effect for terfenadine 120mg administered twice daily for 25 days against hyperventilation-induced bronchoconstriction (Badier et al. 1988). In 20 asthmatic children, a single terfenadine 60mg dose improved resting FEY I by 32% 3 hours after administration, but after exercise, when values of PEFR were normalised to placebo baseline, terfenadine showed no protective effect against exercise-induced bronchoconstriction (MacFarlane & Heaf 1987). The response to skin prick tests with allergen was inhibited by 64% after pretreatment with a single terfenadine 180mg dose in 9 adult atopic patients (Rafferty et al. 1987), and at a dosage of 30mg twice daily 10 times more allergen was required to produce a weal similar in size to that seen in children (aged 6 to 12 years) administered placebo for 7 days (Kjellman & Andersson 1986). 1.3 Psychomotor Performance, Reactivity and Sedation Studies Numerous studies comparing terfenadine 60mg administered orally as a single dose, or as twice daily doses for 2 or 3 days, with other histamine H I-receptor antagonists or placebo in healthy volunteers show that terfenadine lacks depressant effects on the central nervous system (table I) . Compared with placebo, terfenadine did not impair psychomotor performance (assessed by a battery of tests including auditory and visual reaction

557

time, pursuit rotor performance, critical flicker frequency , visuomotor coordination, driving performance and the digit symbol test) or alter subjective assessment of alertness , well-being, mood or drowsiness even at dosages up to 600 mg/day for 7 days (table I). Furthermore, Gastpar and Dieterich (1982) reported no sedation in 15 patients treated with terfenadine 60mg twice daily for 3 months in a single-blind study. Other so-called nonsedating antihistamines, such as loratadine, astemizole and azatadine, also did not differ from placebo in these evaluations (table I). By comparison, classic histamine HI-receptor antagonists, such as diphenhydramine, chlorpheniramine, or triprolidine, markedly depressed central nervous system function when administered at recommended therapeutic dosages. Assessment of EEG profiles during terfenadine treatment has shown that the drug failed to provoke the EEG changes characteristic of sedation , decreased attention, or impaired cerebral processing speed (Fink & Irwin 1979; Meador & Loring 1988). In contrast, in these studies, diphenhydramine and chlorpheniramine increased slow wave activity in a manner characteristic of compounds with sedative behavioural effects. Several single-dose studies have investigated the influence of concomitant administration of terfenadine and other histamine HI-receptor antagonists on the effects of centrally acting depressants in healthy volunteers (table I). Terfenadine did not potentiate the depressant effects of diazepam or alcohol as assessed by visual reaction time, tracking tests, driving performance, or subjective feelings of alertness or drowsiness. Similar findings were observed with coadministration of loratadine and diazepam , and acrivastine and alcohol. Psychomotor performance deteriorated during administration of clemastine plus diazepam , and diphenhydramine plus alcohol (table I). In a multidose study, neither terfenadine 120 rug/day nor loratadine 10 rug/day for 4 days influenced the central depressant effect of alcohol on driving performance (table I).

Drugs 39 (4) 1990

558

Table I. Some randomised double-blind placebo-controlled studies of psychomotor performance , reactivity and sedat ion in healthy volunteers after administration of terfenadine (T) as single or multiple doses, alone or comb ined with other centra l nervous system (CNS) depressants Reference

No. of volunteers

Single-dose studies Gaillard et al. (1988)

Drug and dosage (mg); (duration) [days)

Results'

T 60

T=P L = P CI > P

L 10

Cll

T 60

Moskowitz & Burns (1988)

T ""P O >P

050 Nicholson & Stone (1982)

T 60 As 10, 20 Tri 10 SR

O'Hanlon (1988)

20

T 60 L 10, 20 Tri 10 SR

MUltiple-dose studies Aso & Sakai (1988)

10

Betts et al. (1984) Brandon & Weiner (1980)

31 36

34 Kulshrestha et al. (1978)

12b

Luscombe et al. (1983) Combined with other CNS depressants Cohen et al. (1987) Gaillard et at . (1988)

16

O'Hanlon (1988)

a

16

=

T = pc L = pc Tri > pc

06

T = pc 0 > pc

T 60 bid (2) Tri 5 tid (2)

T = pc Tri > pc

T 60

r,

20 tid (7) T 2 200 tid (7) Ch 4 tid (7) T 60 bid (3) Ch 4 tid (3)

T=P Ch > P (3 of 6 tests)

T 60 bid (3) Az 1 bid (3)

T=P Az = P

T 60 or 120 + Alee; sd Ac 4 or 8 + Alee; sd

T + Ale = P + Ale Ac + Ale = P + Ale

T 60

+ Oi 5: sd

L 10

Oi 5: sd Di 5: sd

Cll Moser et al. (1978)

T=P As P Tri > P (4 of 6 tests)

+

+

T + Oi = P + Oi L + Oi = L + Oi CI + Oi > P + Oi

T 120 + Oi 10; sd o 100 + Oi 10: sd

T+Oi=P+Oi 0+ Oi > P + Oi (10 of 11 tests)

T 60 bid + Alee (4) L 10 od + Alee (4)

T + Ale = P + Alec L + Ale = P + Alec

Psychometric performance assessed using , among others , aud itory/visual react ion time, pursuit rotor test , critical flicker frequency, vlsuomotor coordination. digit symbol test. Alertness, well-being and drowsiness assessed SUbjectively. b Crossover study. c Results based on assessment of actual driVing performance. d Single -blind. e Alcohol 32m I or to a target blood concentration of 0.07g{100ml. Abbreviations and key: L = loratadine: CI = clemastine; Ac = acrivastine: 0 = diphenhydramine: As = astem izole ; Tri = triprolidine : Ch = chlorpheniram ine; Az = azatadine: Ale = alcohol : Oi = diazepam; SR = sustained release : bid = twice daily ; tid = 3 times daily : sd = single dose : od = once daily: P = placebo: A = B indicates an equal depressant act ivity : A > B indicates A had significantly more depressant activity: A < B indicates A had significantly less depressant act ivity ; A "" B indicates A tended to be less depressant.

Terfenadine : An Updated Review

1.4 Pharmacokinetic Properties Single-dose pharmacokinetic studies of terfenadine have been undertaken in healthy adult volunteers using radioimmunoassay to detect plasma terfenadine concentrations (lower sensitivity limit 0.2 ~g/L) [Cook et al. 1980; Garteiz et al. 1982; Van Landeghem et al. 1980]. Since the initial review of the drug (Sorkin & Heel 1985), additional data have become available on the pharmacokinetics of terfenadine . However, the disposition of the drug in adult patients remains to be clarified. 1.4.1 Healthy Volunteers Terfenadine is rapidly absorbed after a single oral 60 or 180mg dose: mean peak plasma terfenadine concentrations of 1.5 ~g/L were determined by radioimmunoassay after a 60mg dose and peak concentrations of 4.5 ~g/L were recorded about I hour after a 180mg dose (Garteiz et al. 1982). Okerholm et al. (1981) reported that AVC and peak plasma terfenadine concentrations determined by radioimmunoassay were linearly correlated with dose over a range of 60 to 180mg. Sensitive, specific HPLC methods have confirmed that peak plasma levels of unchanged terfenadine are generally less than 10 ~g/L after single and multiple doses of up to 240 mg/day (unpublished data on file, Merrell Dow Pharmaceuticals). Peak plasma radioactivity concentration was 351 ~g/L after 1.67 hours in adult volunteers administered a single 14C-terfenadine 60mg dose as an oral suspension (Okerholm et al. 1981). In a material balance study, approximately 40% of orally administered 14C-terfenadine was excreted in urine and 60% was recovered in faeces within 12 days (Woodward & Munro 1982; unpublished data on file, Merrell Dow Pharmaceuticals). 14C-terfenadine followed typical biphasic kinetics with a distribution half-life of 3.6 hours and an elimination half-life of 16 to 23 hours. A comparison of plasma data obtained by radioimmunoassay and data obtained following administration of a single 14C-terfenadine 60mg dose indicates that the absorption of terfenadine is

559

greater than would be assumed based on radioim munoassay data, and that extensive biotransformation of terfenadine occurs after oral administration. Peak plasma 14C-terfenadine concentrations and AVC values were about 200 times higher than those based on radioimmunoassay data (Garteiz et al. 1982). The tissue distribution of terfenadine has not been investigated in human studies; in rats and dogs radioactivity levels were highest in liver and lung tissue and lowest in blood and brain tissue after a single oral or intravenous dose of 14C-terfenadine (Leeson et al. 1982). Terfenadine is rapidly and extensively (> 99%) metabolised to 2 major metabolites; a carboxylic acid derivative (metabolite I) which is the product of oxidation and has approximately one-third of the in vitro antihistaminic activity of terfenadine, and a piperidine-carbinol derivative (metabolite II) which has no apparent antihistaminic activity (fig. 2). Metabolites I and II accounted for 71% of recoverable urinary radioactivity, with metabolite I accounting for 49% of the radioactivity recovered in faeces and only a trace attributable to unchanged terfenadine (Garteiz et al. 1982). Metabolite I is detectable in plasma within 30 minutes of administering a single oral terfenadine 60mg dose and peak plasma concentration is reached after approximately 3 hours (Woodward 1989). Terfenadine is extensively (97%) bound to human serum proteins, while metabolite I is only 70% bound. Following administration of single oral 60, 120 and 180mg terfenadine doses, metabolite I peak plasma concentrations and AVC values increased linearly with dose. Multiple dose studies, including regimens of 60mg twice daily, 120mg daily, and 120mg twice daily, confirmed dose proportionality (unpublished data on file, Merrell Dow Pharmaceuticals). The terminal elimination half-life of metabolite I determined from single and multiple dose studies was approximately 17 hours (Woodward 1989). Plasma concentrations of metabolite I are not significantly affected by food and are not vastly different in elderly as opposed to young adults (Woodward 1989).

560

Drugs 39 (4) 1990

Fig. 2. Metabolic transformation of terfenadine in humans to its 2 major metabolites (after Garteiz et al. 1982).

The bioavailabilities of oral terfenadine administered as a fast-dissolving tablet or liquid suspension were not significantly different (Van Landeghem et al. 1980; unpublished data on file, Merrell Dow Pharmaceuticals). As has been previously reported for other histamine H (-receptor antagonists (Simons & Simons 1983; Simons et al. 1986) mean peak plasma concentrations of metabolite I preceded the maximum suppression of histamine-induced weal response by I to 3 hours (Simons et al. 1987, 1988; unpublished data on file, Merrell Dow Pharmaceuticals).

1.4.2 Children with Allergic Rhinitis The pharmacokinetics of terfenadine have been studied in children (mean age 7 years) with seasonal allergic rhinitis (Simons et al. 1987). Plasma concentrations of metabolite I were measured after a single oral dose of terfenadine suspension 15mg (children < 15kg bodyweight), 30mg (15 to 30kg bodyweight), or 60mg (> 30kg bodyweight). The mean maximum plasma concentration of metabolite I was 242 Ilg/L after 2.3 hours. As has been found with other histamine H I-receptor antagonists (Simons et al. 1982, 1984), the mean elimin-

ation half-life may be shorter in children than in adults.

2. Therapeutic Trials Since the initial review of terfenadine appeared in this Journal (Sorkin & Heel 1985), additional studies have compared the efficacy of terfenadine with other histamine HI-receptor antagonists (in particular those with nonsedating propert ies) and with antiallergic agents such as sodium cromogIycate (cromolyn sodium) and inhaled corticosteroids in patients with seasonal allergic rhinitis. These investigations were conducted as doubleblind, parallel group studies and most were placebo-controlled and involved large numbers of patients. Fewer studies have investigated the therapeutic efficacy of terfenadine in perennial allergic rhinitis, but the drug has been compared with placebo, loratadine, asternizole, chlorphenirarnine, cetirizine , and ketotifen in a few double-blind studies. Evaluation of symptoms of allergic rhinitis (nasal congestion, rhinorrhoea, sneezing, itchy nose/ eyes/throat, lacrimation, red eyes) was generally based on subjective methods. Rhinomanometry or


the use of a back-up medication were used to evaluate efficacy in some studies. Terfenadine has also been evaluated in atopic patients with bronchial asthma or allergic dermatological disorders and, to a lesser extent, in patients with the common cold. 2.1 Seasonal Allergic Rhinitis 2.1.1 Noncomparative and Placebo-Controlled Studies Noncomparative clinical studies reported in the early 1980sshowed that oral terfenadine 60mg twice daily produced good or very good symptomatic relief in over 80% of the approximately 200 patients studied, and prevented episodes of allergic rhinitis when used prophylactically over a 6-month period (Fuentes-Gonzalez et al. 1981; Gastpar & Dieterich 1982; Meyer & Garten 1982). More recently, a multicentre study in 179 patients reported moderate or complete relief of rhinitis symptoms in 86% of patients after I week of treatment with terfenadine 60mg administered twice daily, and in about 90% of patients still enrolled after up to II weeks of treatment (Kemp et al. 1988). In a few double-blind studies which compared the efficacy of terfenadine and placebo in adults and children over I or 2 weeks, global improvement was rated as good or excellent in 60 to 85% of patients treated with terfenadine 15 to 60mg twice daily and in 29 to 60% of placebo recipients (table II). Guill et al. (1986) reported maximum symptomatic improvement (particularly with respect to sneezing and rhinorrhoea) after 3 days of treatment in children. The high placebo response rate in this study (60% of patients responded to placebo) may reflect a decrease in the pollen count during the stud y period, or may be due to the fact that parents , and not the patients themselves, rated symptomatic improvement. Comparative studies of terfenadine and other histamine H I-receptor antagonists which included a placebo group have confirmed the overall superiority of terfenadine over placebo in ameliorating most nasal and ocular symptoms (table III) with

561

the possible exception of nasal congestion (Howarth & Holgate 1984; Pastorello et al. 1987; Rombaut et al. 1986). 2.1.2 Dosage Regimen Studies Terfenadine 60mg administered twice daily was as effective as a single 120mg dose in patients with seasonal allergic rhinitis (Henauer et al. 1987; Yamate et al. 1988). 81% of patients receiving once daily terfenadine versus 84% of those.treated with twice daily terfenadine showed complete or marked relief of symptoms after I week (Henauer et al. 1987). In another study, symptom relief was good or complete in 55% of 39 patients receiving terfenadine 60mg twice daily versus 62% of 38 patients treated with 120mg twice daily (Murphy-O'Connor et al. 1984). Symptom relief was achieved within I to 2 hours in both treatment groups, thus it appears that there is no advantage in increasing the daily dosage of terfenadine in patients with seasonal allergic rhinitis. 2.1.3 Comparisons with Other Histamine H j-Receptar Antagonists Table III summarises some double-blind, short to medium term (I to 8 weeks' duration) studies which compared terfenadine with alternative histamine HI-receptor antagonists. These studies support findings of earlier comparative studies which were reported in the initial review of terfenadine in this Journal (Sorkin & Heel 1985). Based on patients' or investigators' evaluation of overall efficacy (percentage of patients achieving good or complete global assessment), improvement in nasal or ocular symptoms, and patients' willingness to receive similar treatment in the future, terfenadine 60mg twice daily was comparable to chlorpheniramine 4mg 3 times daily, loratadine 10 or 40 mg/day , and mequitazine 5mg twice daily, and was superior to clemastine Img twice daily (table III). Although terfenadine 60mg twice daily was as efficacious as dexchlorpheniramine 6 mg/ day, when a higher dexchlorpheniramine dosage (12 mg/day) was administered in patients exposed to a high pollen count, terfenadine 60mg twice daily was significantly less effective at improving nasal

Drugs 39 (4) 1990

562

Table II. Some randomised double-blind studies comparing oral terfenadine (T) and placebo (P) in children (aged 3 to 12 years) and adults with seasonal allergic rhinitis Reference

No. of patients

Studies in children Guill et al. (1986) 68 b

Terfenad ine dosage (mg)

35

T 30-60 bidc P

Lockhart & Maneksha (1983)

58 55

T 15-30 bidc P

Molkhou & Beaumont (1985)

40 40

T 30 bidc P

55 55

T 60 bid P

Studies in adults Kagan et al.

(1980)

Duration of treatment (weeks)

Results

% improvement in total symptom score

% patients with good! complete global assessment investigator

patient

T > pd

85' 60

2

58" 30

62' 29

58' 40

60' a 40

overall efficacya

67" 31

T >P T >P

76' 441

T >P

a Based on individual symptom improvement , patients ' and investigators' global assessment and incidence of adverse effects . b Multicentre study. c Terfenadine administered orally as liquid suspension. d For rhinorrhoea, nasal congestion and sneezing . e Global assessment by patient . parent and investigator. f Results of patients who did not open escape envelope containing chlorpheniramine during study. Abbreviations and key: bid = twice daily; T > indicates terfenadine produced a superior response . Statistically significant difference versus placebo : ' p < 0.05; " P "" 0.01.

and ocular symptoms (Gutkowski et al. 1988). The overall tolerability of terfenadine was at least as good as placebo and other nonsedating antihistamines in these studies (see section 3). Studies comparing terfenadine with astemizole , another nonsedating histamine H (-receptor antagonist, have been less conclusive. Both terfenadine 60mg twice daily and astemizole 10 mg/day alleviated nasal and ocular symptoms (with the exception of nasal congestion) compared to pretreatment levels, but terfenadine appeared less effective than astemizole with regard to relieving itchy eyes, sneezing, rhinorrhoea and nasal congestion after 8 weeks of treatment in 1 study (Howarth & Holgate 1984). Interpretation of the results of this study is complicated by the ad libitum use of a back-up antihistamine, consumption of which was not detailed. Asternizole 10 rug/day provided more ef-

fective protection against symptoms of allergic rhinitis after 4 and 8 weeks (Rombaut et al. 1986). However, terfenadine 60mg twice daily had a faster onset of action than astemizole (median 3 vs 48 hours), although after 8 days no significant difference in efficacy was seen between treatment groups (fig. 3). Thus , studies in which treatment is administered for less than 1 week may not be sufficient to demonstrate the full efficacy of astemizole; this may explain the inconsistent findings of studies comparing terfenadine and astemizole. Terfenadine 30mg twice daily and astemizole l rng twice daily, both administered as an oral suspension, have been compared in 62 children (aged 6 to 12 years) with seasonal allergic rhinitis (Grillage et al. 1986). In this multicentre, randomised, single-blind study, terfenadine and astemizole sig-


563

nificantly reduced nasal and ocular symptoms (assessed on visual analogue scales) with no significant differences between groups after 4 or 8 weeks. In contrast, assessment of global efficacy by patients (at 8 weeks) and by investigators (at 4 and 8 weeks) indicated significantly better symptom control in the astemizole group. Other studies have shown that the antiallergic and antipruritic efficacy ofterfenadine 30 to 60 rng/ day in children is at least comparable to ketotifen I to 2 rug/day and clemastine (0.5 to 0.75 mg/day) [Varonier & Dieterich 1984; Wuthrich et al. 1984].

2.1.4 Comparisons with Other Antiallergic Agents Terfenadine has been compared with other antiallergic agents, such as the inhaled corticosteroids beclomethasone dipropionate and flunisolide , and with sodium crornoglycate, in a few studies. Oral terfenadine 60mg twice daily and beclomethasone dipropionate aerosol 400 ltg/day markedly reduced symptoms of rhinitis in a total of 40 patients as assessed by patients and investigators after 4 weeks (Beswick et al. 1985). Terfenadine

c

*

100

(n=15)

~

~

80

**

~

8

(n= 15)

Ol

g> C 60

.~ ~ ,g ~

0 a a; .5 ~(ij a..g '"

J!l

40

(n= 16)

if. OJ 20

Day 2

Day 8

Fig. 3. Percentag e of pat ients with seaso nal allergic rhin itis j udged to ha ve good/e xcellent global improvement by investigato rs after 2 or 8 days of treatment with placebo (0 ), terfenadin e 60mg twice daily (_). or astemizole 10 mg/da y (D) in a rand omi sed. double-bl ind study. Stat istical significance indica ted by • p < 0.05 I'S asternizolc; •• p < 0.0 1 I'S placebo (after G irard et al. 1985).

provided more effective relief of ocular symptoms but , not surprisingl y, was less effective in reducing nasal symptoms (with the exception of sneezing). However, the use of additional medication to relieve ocular symptoms was similar in both groups. Most patients in each group considered their symptoms to be well controlled but both physicians' and patients' assessment of overall symptom control favoured beclomethasone dipropionate. A similar pattern of response was seen in patients treated with oral tcrfenadine 60mg twice daily or inhaled flunisolide 200 ltg/day (Dickson & Cruickshank 1984). After 3 weeks, flunisolide produced significantly more relief from sneezing and nose blowing and less relief of ocular symptoms. After 7 weeks, overall control of symptoms was significantly better in flunisolide recipients. Improvement in nasal symptoms was enhanced during II weeks of concomitant administration of terfenadine 120 mg/day and inhaled flunisolide 200 ltg/day compared with terfenadine administered alone (Backhouse et al. 1986). Little difference was apparent in the control of ocular symptoms in the terfenadine versus terfenadine plus flunisolide groups . Sodium cromoglycate eye drops 2% (total daily dose 3.2mg) appeared superior to oral terfenadine 60mg twice daily in providing both relief of ocular symptoms in adults patients with seasonal allergic conjunctivitis, and speed of onset of symptom relief (Riddington 1989). However both drugs provided similar relief of symptoms as judged by individual symptom scores. Moderate or complete relief from symptoms was reported in 76% of patients treated with a combination of terfenadine 60mg twice daily and sodium cromoglycate 2% I puff/nostril 4 times daily for I week followed by 5 weeks of treatment with sodium cromoglycate alone (Lindsay-Miller & Chambers 1987). By comparison, 53% of patients receiving monotherapy with terfenadine 60mg twice daily for 6 weeks had moderate or complete relief of symptoms. During combination treatment, significantl y (p < 0.00 I) greater relief of nasal congestion and rhinorrhoea was achieved , and this persisted for the remainder of the stud y, suggesting that the

Drugs 39 (4) 1990

564

Table III. Some randomised, double-blind, parallel group studies comparing terfenadine (T) with placebo (P) and other histamine HI-receptor antagonists in patients with seasonal allergic rhinitis Reference

Astemizole (A) Girard et al.

(1985) Howarth & Holgate (1984) Rombaut et al,

(1986)

No. of patients

16 15 16 32 d 30 d 28d 52 45

Chlorpheniramine (Ch) Buckley et al. 69

(1988)

Kemp et al,

(1985) Clemastine (C) Gastpar et al,

(1988)

Pastorello et al.

(1987)

Loratadine (L) Gutkowsk i et al.

(1988)

Horak et at,

(1988) Mequitazine (M) Hugonot et al.

(1986)

T 60 bid A 10 od P T 60 bid A 10 od P T 60 bid A 10 od

71 75 113 119 119

T 60 bid Ch 4 tid P T 60 bid Ch 4 tid P

28 26 29

T 60 bid C 1 bid P

Dexchlorpheniramine (0) 87 Gutkowsk i et al.

(1985)

Dosage (mg)


Results excellent/good global assessment (% pts)

symptom severity scores

patient

investigator

nasals

ocuiar>

63· 67" 13

T =A >P

T=A >P

T=A=P

T = P < A9

T = P < AI

T=A

8 4

87 33 32

T 60 bid D 6 bid T 60 bid D 2 tid

2

88 91 83 89 87 80

T 60 L 40 P T 60 L 10 P

bid od

2

bid od

2

69 72

T 60 bid M 5 bid

overall tolerability"

57 67

55 71

T = A9

T=A

T =A

60h.. 66h .. 45 h 64h .. 65h .. 36h

70·· 73·· 48 60·· 60·· 30

T=Ch >P

T=Ch >P

T=P >Ch

T = Ch > P

T = Ch > P

T = P ;;' Ch

71·· 46·· 31

T;;'C=P

T;;' C= P

T =P >C

40 64 78 73

T D

T =L >P

T =L >P

T=L > P

T=L >P

T=L >P

T=L=P

T= M

T= M

T> M

73i· 8()j· 31i

36i 53· i 33i 65· 67" 16 65 54

a Rhinorrhoea, nasal congestion, nasal itch, sneezing, difficult breathing. b Lacrimation, itch, red eyes. c Based on incidence of sedation, somnolence and fatigue. d Clemastine lmg was available to all patients as rescue medication. e Rhinorrhoea and sneezing only. f Itchy eyes only. g Except nasal congestio n and difficult breathing. h Percentage of patients willing to take medication again. i Improvement at end-point (last valid visit for all patients). Percentage of patients reporting symptomatic relief after 3 days. j Abbre viations and key: bid = twice daily; od = once daily; tid = 3 times daily; T < indicates terfenadine had a significantly inferior response ; T 'i'; indicates a tendency for terfenadine to have an inferior response ; T = indicates an equal response; T > indicates a significantly superior response; T ;;. indicates a tendency for terfenadine to have a superior response. Statistically significant difference versus placebo: • p < 0.01; •• P < 0.001; absence of notation indicates results were not significantly different or no p-values were provided.


2 drugs have an additive effect in patients with seasonal allergic rhinitis. 2.2 Perennial Allergic Rhinitis The efficacy of terfenadine in patients with perennial allergic rhinitis has been less extensively studied. A few, mainly double-blind parallel group studies , have compared terfenadine with placebo, ketotifen , chlorpheniramine, loratadine, cetirizine, astem izole or inhaled beclomethasone dipropionate over 2 or 4 weeks. Agbayani et al. (1981) found terfenadine 60mg twice daily to be comparable to placebo in providing relief of symptoms in 35 patients: 36 and 23% of terfenadine and placebo recipients , respectively, had complete symptom relief and 14 and 23%, respectively, had no symptom relief. These results should be interpreted with caution since the number of patients evaluated for efficacy was too small to permit statistical analysis and pretreatment groups were not comparable with regard to the severity of rhinorrhoea or throat symptoms. However, other studies that included an active and a placebo control group have demonstrated superior efficacy for terfenadine over placebo (table IV). Terfenadine 60mg administered twice daily was not significantly different from ketotifen Img twice daily, loratadine 10 rug/day, chlorpheniramine 8mg twice daily or cetirizine 10 mg/day in providing relief of rhinitis symptoms after 2 to 4 weeks but was less effective than astemizole 10 rug/day after 4 weeks in reducing most symptoms despite having a similar effect after 2 weeks of therapy (table IV). Although terfenadine and cetirizine were equally effective in reducing symptoms, more patients preferred cetirizine versus terfenadine. Of the 28 patients studied, only 2 terfenadine and no cetirizine recipients discont inued treatment due to lack of efficacy (Schmeisser et al. 1989). Oral terfenadine and inhaled beclomethasone dipropionate were effective in patients with perennial rhinitis, however, beclomethasone appeared superior, part icularly with regard to relief of rhinorrhoea, sneezing and nasal mucosa swelling and erythema, and more patients (69 vs 15%) preferred beclo-

565

methasone versus terfenadine (Robinson et al. 1989). 2.3 Allergic Dermatological Disorders Urticaria is a relatively common dermatological condition which may be attributed to allergic, physical, infectious or autoimmune aetiologies but is frequently idiopathic. Histamine HI-receptor antagonists have been successfully used to relieve the symptoms of urticaria, typically pruritus and erythema, but their use has been limited by their propensity to cause depression of the central nervous system. Terfenadine has been compared with placebo, and alternative histamine H I-receptor antagonists , and has been evaluated in combination with a histamine Hj-receptor antagonist, in patients with chronic urticaria. The drug has also been compared with ketotifen in children with atopic dermatitis. Double-blind studies in over 250 patients with chronic urticaria have shown that terfenadine 60mg twice daily is as effective as a single 120mg dose with regard to reducing pruritus and number and size of weals in chronic urticaria , with no significant differences seen between dosage regimens (Henauer et al. 1989). Unlike placebo, terfenadine 60mg twice daily produced marked or complete relief of itch, number and size of weals after I week of treatment (Cerio & Lessof 1984; Ferguson et al. 1985; Salisbury & Blair 1987). In I study, improvement was sufficient for 2 patients with intractable urticaria to discontinue corticosteroid therapy (Cerio -& Lessof 1984). Double-blind randomised clinical studies of I to 6 weeks' duration which evaluated terfenadine and other histamine H I-receptor antagonists are summarised in table V. Based on an overall (global) assessment of efficacy terfenadine 60mg twice daily was as effective as brompheniramine 12mg twice daily (except in patients with dermatograph ism who responded better to brompheniramine, or cetirizine 10 rug/day), tended to be better than chlorphenamine 4mg 3 times daily or c1emastine Img twice daily, but was less efficacious than astemiz-

566

Drugs 39 (4) 1990

Table IV. Some double-blind studies comparing terfenadine (T) with placebo (P) and alternative active treatments in patients with perennial allergic rhinitis Reference

No. of patients

Dosage (mg)


Results moderate/excellent global assessment (% patients) investigator

Placebo Agbayani et al. (1981) Astemizole (A) Boland (1988) Cetirizine (C) Schmeisser et al. (1989)

22 b 13b

T 60 bid P

4

64 62

14 13

T 60 bid A 10 od

4

36 66

28c

T 60 bid C 10 od P

2

36 43

T 60 bid C 8 bid P

2

T 60 bid K 1 bid

4

85e 81e

T=K

T 60 bid L 10 od P

4

57 63 26

T=L >P

Chlorpheniramine (Ch) Brostoff & Lockhart 16 (1982) 17 15 Ketotifen (K) Saito et al. (1987)d 75 67 Loratadine (L) Bruttmann et al. (1989)

patient

overall symptom severity score at end of treatment-

68

73 74

T=P

42 69

T P

T = Ch > P

a Based on physician and/or patient assessment of global improvement. b Pretreatment groups not comparable for rhinorrhoea . throat symptoms. c Crossover study . d Reported as an abstract. e Not specified if patient or invest igator assessment. Abbreviations and key: bid = twice daily ; od = once daily ; T = indicates an equal response; T < indicates terfenadine had an inferior response ; T > indicates terfenadine had a superior response.

ole 10 rng/day or azatadine 1mg twice daily. Indeed, astemizole caused a more rapid and persistent decrease in pruritus and erythema scores, and in the size, number or frequency of papules compared with terfenadine (Cainelli et al. 1986). Onset of action was similar in both treatment groups; however, the efficacy ofterfenadine decreased after about 3 weeks while that of astemizole persisted during the 4-week study . A double-blind study reported as an abstract, and consequently lacking in details of methodology and results, has shown that

terfenadine 60mg twice daily and hydroxyzine 25mg 4 times daily produced similar relief of pruritus, erythema and number of weals in patients with chronic urticaria (Boggs et al. 1988). Paul and Bodeker (1986) investigated the effect of combining twice daily terfenadine 60mg with ranitidine 150mg twice daily, a histamine Hj-receptor antagonist, in 45 patients with chronic idiopathic urticaria. After 9 days, patients receiving this combined therapy reported better relief of itching than patients treated with terfenadine or ranitidine


alone; combined treatment was not significantly different from terfenadine monotherapy in improving severity of wealing. Combined treatment' may, therefore, provide additional symptomatic relief in patients who are not adequately controlled with a histamine H r-receptor antagonist. In early studies terfenadine had no effect on pruritus associated with atopic eczema or psoriasis (see for example Krause & Shuster 1983). More recently, Doherty et al. (1989) have demonstrated that administration of terfenadine 60mg or acrivastine 8mg 3 times daily for 10 days significantly reduced itching compared with placebo, and caused a slight but clinically relevant overall improvement as assessed by patient or investigator in 49 patients with atopic eczema. Since both drugs have no major sedative effect and are known to act via antagonism of histamine H I-receptors, the authors suggest that histamine has an active role in pruritus associated with atopic eczema. Similarly, in 29 children (aged 3 to 12 years) with atopic dermatitis, terfenadine 30 to 60 rug/day and ketotifen I to 2 rug/day, administered as oral suspensions, produced marked improvement in pruritus, excoriation, eczema, erythema, and sleeplessness within 2 weeks (Tholen & Dieterich 1989). Pruritus associated with chronic liver disease has been treated successfully with terfenadine 60 to 180mg daily for 2 weeks in 8 patients (Duncan et al. 1984). In this single-blind crossover study, terfenadine and cholestyramine (4 to 12 g/day) reduced mean cumulative pruritus scores to 15.8 and 12.9, respectively: both scores were significantly lower than those seen after chlorpheniramine 4 to 12 rug/day (19.8) or placebo (20.3). 2.4 Bronchial Asthma The role of histamine as a mediator of airway hyper-responsiveness has been recognised for several years, but the routine use of histamine H [receptor antagonists in patients with asthma has been limited by the sedative and anticholinergic adverse effects associated with the high dosages of drug required in this therapeutic area. Since the development of nonsedating histamine antagon-

567

ists, such as terfenadine, the role of histamine H 1receptor antagonism in asthma has been reassessed. Two double-blind crossover studies have compared the efficacy of terfenadine and placebo in patients with stable mild atopic asthma (Rafferty et al. 1988; Taytard et al. 1987). These studies showed that terfenadine at dosages of 120mg twice daily or 180mg 3 times daily reduced the intensity of asthmatic symptoms and the requirement for inhaled bronchodilators, and improved pulmonary function assessed by twice-daily PEFR values compared with placebo. Differences between treatment groups were not large but achieved statistical significance in some instances . A multicentre study in 212 Japanese patients demonstrated greater global improvement and improvement in asthmatic symptoms, sputum score and degree of impaired sleep in asthmatic patients treated for 10 weeks with terfenadine 120 or 240 rug/day compared with those who received ketotifen 2 rug/day (Makino et al. 1988b). In another study, no significant difference in efficacy was evident after 4 weeks' treatment with terfenadine 120 or 240 mg/day in 89 patients with bronchial asthma (Makino et al. 1988a). These results, and the precise role of terfenadine in the treatment of asthma relative to established antiasthmatic agents, remain to be confirmed with wider clinical experience. 2.5 Common Cold The few studies that have evaluated the efficacy of histamine HI-receptor antagonists in the symptomatic relief of the common cold have provided inconclusive evidence for the possible role of histamine in the pathogenesis of this condition (Crutcher & Kantner 1981; Howard & Kantner 1979; West et al. 1975). Two studies have compared terfenadine 60mg administered twice daily for 4 days, or three 60mg doses administered 12 hours apart, and placebo in patients with a recent onset of common cold symptoms but no history of allergic rhinitis (Gaffey et al. 1988; Henauer & Gluck 1988). Treatment was started within 6 to 48 hours of the onset of symptoms. After three 60mg

568

Drugs 39 (4) 1990

Table V. Some double-blind randomised clinical stud ies comparing terfenadine (T) with other histamine HI-receptor antagonists in patients with chronic urticaria Reference

No. of patients

Dosage (mg)

Results


overall efficacya

% improvement from baseline

(% patients good/ excellent global

pru ritus

no. of weals

erythema

T"'A (T 55 vs A 77)

66 75

60 72

78

1-1.4

T < Az

50 69

55 60

45 76

2

T

2

T=C

30 46

32 52

6

T

2

T ~

improvement) Astemizole (A) Cainelli et al. (1986) Azatadine (Az) Neumann (1984)

20 22

T 60 bid

24 27

T 60 bid

Brompheniramine (B) Ormerod et at, 16b C (1986) Cetirizine (C) Go et at, (1989)

28 b

4

A 10 od

Az 1 bid

T 60 bid

= Be

56'66'-

B 12 bid d

T 60 bid C 10 od

64

P Chlorpheniramine (Ch) Grant et al. (1988)

Clemastine (CI) Bazex et al. (1982) Fredriksson et al. (1986)

45 40 35

T 60 bid

47 47 42 54 bh

T 60 bid

~ Ch (T 83 vs C 71)

Ch 4 tid

CI

ens

T

~

T

= clg

T = clg

(T 60 vs CI 49)

Cll bid

P T 60 bid

T

2

~

T > clg

CI

Cll bid P

a Based on physician and/or patient assessment of global improvement. b Crossover study. c 10 patients had urticaria with dermatographism . d Sustained release formulation. e Except in patients with ·urticaria with dermatographism, in whom terfenadine was less effective than brompheniramine. f Symptoms of itch and rash reported collectively. g Percentage symptomatic improvement not given . h Patients had access to diphenhydramine 25mg . Abbreviations and key: bid = twice daily ; od = once daily: tid 3 times daily : P placebo; T '" indicates a tendency for terfenadine to have an inferior response : T < indicates terlenadine had a significant inferior response: T = indicates an equal response; T ~ indicates a tendency for. terfenadine to have a superior response; T > indicates terfenadine had a significant superior response. Statistically significant difference versus baseline: - p < 0.01.

=

doses, terfenadine produced moderate to excellent improvement in 63% of recipients versus 40% of placebo recipients, and significantly improved na-

=

sal swelling, obstruction and redness compared to placebo (Henauer & Gluck 1988). However, in another study in which patients re-

569


ceived either terfenadine 60mg twice daily for 4 days or placebo both groups had similar symptom scores, and after 3.5 days 31% of terfenadine recipients and 34% of placebo recipients reported complete or marked symptom relief (Gaffey et al. 1988). Complete symptom relief was more common in the placebo group (10% vs 3%).

3. Adverse Effects The adverse effect profile ofterfenadine was established previously in this Journal (Sorkin & Heel 1985) and has been confirmed in more recent clinical studies. Most adverse effects have been mild and have not required withdrawal of treatment. Barlow et al. (1982) reviewed the incidence of adverse effects in 965 patients with allergic rhinitis and allergic dermatoses treated with terfenadine 120 to 400 rug/day in clinical studies of between 2 days' and 3 months' duration, all but 2 of which were double-blind. The incidence of sedation and related effects (drowsiness, sleepiness, fatigue, weakness, lack of concentration) was 12.6%and was virtually the same as the incidence in placebo recipients (n = 729; 11.4%) and almost half that seen in patients treated with chlorpheniramine 12 or 16 mg/day, clemastine 2 rug/day or dexchlorpheniramine 6 mg/day, More recent studies have confirmed these findings and have shown the incidence of sedation to be similar in patients treated with terfenadine or other nonsedating histamine H I-receptor antagonists such as astemizole, loratadine or mequitazine at recommended therapeutic dosages (table III). The incidence of sedation does not increase with increased terfenadine dosages (up to 600 rug/day) [Brandon & Weiner 1980] or increased duration of treatment (for up to 12 weeks) [Gastpar & Dieterich 1982]. Dry mouth, nose or throat was reported in 2.6% ofterfenadine recipients compared with 2.2% of placebo recipients and 2.7 to 4.6% of patients given chlorpheniramine, dexchlorpheniramine or clemastine (Barlow et al. 1982) while headache has been associated with terfenadine in 9.2 to 18% of patients treated for allergic rhinitis (Agbayani et al. 1981; Buckley et al. 1988; Kemp et al. 1985). Placebo recipients

Table VI. Incidence of adverse effects resulting from tertenadine or placebo administration (unpublished data on file. Merrell Dow Pharmaceuticals) [Sorkin & Heel 1985] Adverse reaction

CNS effects drowsiness fatigue other Autonomic effects Gastrointestinal comp laints Allergy symptoms Skin symptoms Musculoskeletal symptoms Cardiovascular symptoms Genitourinary symptoms Other

Incidence (% of patients) tertenadine (n = 2125)

placebo (n = 1393)

9.0 4.8 10.9

8.4

5.8

3.7

6.5 9.1

5.2

1.2 1.3 1.3

1.1 4.5

2.9 9.5

7.5 1.7 1.0

0.9 0.5 4.2

reported a similar incidence of headache in these studies. Headache is a commonly reported symptom in patients with allergic rhinitis; these incidence rates may therefore not be related to drug therapy. Table VI summarises the incidence of other adverse effects associated with terfenadine treatment as compiled by the manufacturer. There have been case reports of dermatological reactions (exacerbation of psoriasis, urticaria and rash) [Harrison & Stones 1988; Stricker et al. 1986], alopecia (Jones & Morley 1985), angioedema, photosensitivity reaction and desquamation (Stricker et al. 1986), and hepatitis (Larrey et al. 1985) in patients receiving terfenadine, and seizures and cardiotoxicity have been associated with terfenadine overdosage (Davies et al. 1989).

4. Dosage and Administration The recommended dosage of terfenadine in adults is 60mg (I tablet or 10mi of the suspension) twice daily. In children aged 3 to 5 years the suspension formulation is recommended at a dosage of 15mg twice daily and in children aged 6 to 12 years a dosage of 30 to 60mg twice daily, depending on bodyweight, is advised. Dosages up to 540

Drugs 39 (4) 1990

570

rug/day have been used in the treatment of asthmatic patients.

5. Place of Terfenadlne in Therapy Development of the nonsedating class of histamine H [-receptor antagonists, such as terfenadine, provides the clinician with a valuable alternative for treatment of histamine-mediated disorders. Rapid relief of symptoms can be achieved with this group of drugs while avoiding the debilitating adverse effects (particularly central nervous system depression) of the classic histamine HI-receptor antagonists. The efficacy of terfenadine in seasonal allergic rhinitis has been convincingly demonstrated. Terfenadine was superior to placebo and was comparable to other histamine H I-receptor antagonists including chlorpheniramine, loratadine, and mequitazine in double-blind studies. The drug had a more rapid onset of action than astemizole but after about a week this initial advantage was no longer apparent. When compared with inhaled corticosteroids, terfenadine had a more pronounced effect on ocular symptoms but appeared to be less effective in ameliorating nasal symptoms. Concomitant administration of terfenadine and flunisolide (an inhaled corticosteroid) or sodium cromoglycate may enhance the response compared with monotherapy. In children, terfenadine administered as an oral suspension was at least comparable to astemizole, ketotifen and clemastine in providing relief of seasonal rhinitis symptoms. Fewer studies have investigated the efficacy of terfenadine in perennial allergic rhinitis. However, terfenadine does appear to provide symptomatic relief comparable to ketotifen, cetirizine, loratadine and chlorpheniramine in this disorder. In the treatment of allergic dermatological disorders (chronic urticaria, atopic eczema) terfenadine provided symptomatic relief similar to brornpheniramine or cetirizine and tended to be more efficacious than chlorpheniramine or clemastine. Combined treatment with a histamine Hj-receptor antagonist offered additional relief of itching for patients who did not successfully respond to treat-

ment with a histamine HI-receptor antagonist alone. Because terfenadine does not cause significantly more central nervous system effects (particularly sedation) than placebo, even when administered at dosages greater than those recommended, the drug has been evaluated as an antiasthmatic agent using dosages up to 540 mg/day. Subjective asthmatic symptoms, and objective parameters (pulmonary function and frequency of inhaled bronchodilator use) were improved during terfenadine treatment and terfenadine appeared to be superior to ketotifen in I multicentre study undertaken in Japan. Single-dose studies have demonstrated that terfenadine has a pronounced inhibitory effect on bronchoconstriction induced by exercise, or challenge with inhaled allergen in asthmatic patients. However, the role of terfenadine in the treatment of asthma remains to be confirmed in relation to other established antiasthmatic agents. Thus, based on its superior adverse effect profile relative to older antihistamines, combined with comparable efficacy, terfenadine and others of its class should be considered as first-line treatment for the management of allergic rhinitis and chronic urticaria. With wider clinical experience terfenadine may find a similar role in the treatment of other histamine-mediated conditions.

References Agbayani BF. de Guzman F. Roxas J. A comparative study of the safety and efficacy ofterfenadine in perennial allergic rhinitis. Acta Medica Philippina 17: 143-151. 1981 Akagi M. Mio M. Miyoshi K. Tasaka K. Antiallergic effects of terfenadine on immediate type hypersensitivity reactions. Immunopharmacologyand Immunotoxicology 9: 257-Z59. 1987 Aso T. Sakai Y. Effects of terfenadine on actual d riving performance . Japanese Journal of Clinic al Pharmacology and Therapeut ics 19: 681-688 . 1988 Baekhouse CI. Finnamore YP. Gosden CWo Treatment of seaso nal allerg ic rhinitis with flunisolid e and terfenadine. Journal of International Medical Research 14: 35-41. 1986 Badicr M. Beaumont D. Orehck J. Attenuation of hyperventilation-induced bronchospasm by tcrfenadinc: a new antihistamine. Journal of Allergy and Clinical Immunology 81: 437440. 1988 Barlow JLR . Beitman RE. Tsai TH. Terfcnadine, safet y a nd tolerance in controlled clinical trials . Arzneimittcl-Forsehung 32: 1215-1217. 1982

Terfenad ine: An Updated Review

Bazex J. Sans B. Rostin M. Co mparative stud y of terfenad ine in allergic skin of patient s in France. Arzneimitte l-Forschung 32: 1196-1198. 1982 Beswick KBJ. Ken yon GS. Cherry JR . A comparat ive study of beclomethasone di propio nate aqueous nasal spray with terfenadi ne tablets in seaso nal allergic rh initis. Current Medical Research and Opi nion 9: 560-567. 1985 Betts T. Markman D. Debenham S. Mortiboy D. McKevitt T. Effects of two anti hista mine drugs on act ual dr iving performance. British Medical Journal 288: 28 1-282. 1984 Boggs PB. Ellis CN. G rossman J. Washburne WF. G upta AK. et al. A co mparison of terfenad ine and hydroxyzine in the treatment of chro nic urticar ia. Abstract. Proceedi ngs of ACAR meeting. Los Angeles. Novembe r 12-16. 1988 Boland N. A doubl e-blind study of astem izole and terfenadine in the treatm ent of perenn ial rhin itis. Annal s of Allergy 6 1: 1824. 1988 Brand on ML. Weiner M. Clini cal investigation of terfenadine , a nonsedating antihista mine. Annals of Allergy 44: 71-75, 1980 Brion N. Beaum ont D, Adveni er C. Evaluat ion of the antim uscarin ic acti vit y of atropine. terfenadine and mequ itazine in health y volunteers. British Journ al of Clinical Pharmacology 25: 27-32. 1988 Brostoff J. Lockhart JDF. Controlled trial of terfenad ine and chlorph eniram ine maleate in perenn ial rhiniti s. Postgradu ate ' Medical Jo urna l 58: 422-423. 1982 Bruttmann G. Charpin D, Ger mo uty J. Horak F. Kunkel G. et al. Evalu ation of the efficacy and safety of loratad ine in perennial allergic rhin itis. Journ al of Allergy and Clinical Immun ology 83: 4 11-416. 1989 Buckley CE, Buchm an E, Falliers CJ. Segal AT. T inkelman DG. et al. Terfe nad ine treatm ent offall hay fever. Annals of Allergy 60: 123-128. 1988 Cai nelli T. Seidc nari S. Valsecchi R. Mosca M. Double-blind co mparison of aste mizole and terfenadine in the treatm ent of chronic urt icaria. Pharm ath erapeut ica 4: 679-686, 1986 Cerio R. Lessof MH. Tr eatmen t of chro nic idiopathic urt icar ia with terfenad ine. Clinical Allergy 14: 139-141. 1984 Chan T B. Shelton DM. Eiser NM . Effect of an oral H I-receptor antagonist , terfend ine. on ant igen-indu ced asthma . British Jo urna l of Diseases of the Chest 80: 375-384. 1986 Cheng HC, Woodward JK . Antihi stam inic effect of terfenadin e: a new piperidine-type ant ihistamin e. Drug Development Research 2: 181-196, 1982a Cheng HC, Woodward JK . A kinetic study of the antihista minic effect of tcrfenadin c. Arzneimittel-Forschung 32: 1160-1166. 1982b Cohen AF. Ham ilton MJ, Peck AW. Th e effects of acrivastine (BW825C). diphenh ydramine and terfenad ine in combination with alcohol on hum an CNS performance. European Journal of Clinical Pharma cology 32: 279-288. 1987 Cook CEoWilliam s DL. Myers M. Ta llent CR. Leeson GA. et al. Radi oim mu noassay for terfenadine in hum an plasma. Journ al of Pharm aceutical Sciences 69: 1419-1423. 1980 Crutcher J E. Kantn er T R. The effective ness of an tihistamines in the co mmo n cold. Journ al of Clinical Pharm acology 21: 9-15. 1981 Da vies AJ. Harindr a V. McEwan A. Ghose RR. Cardio toxic effect with co nv ulsions in terfenadi ne over dose . British Medical Journ al 298: 325. 1989 Dickson DJ. Cruicks hank JM . Com parison of f1 uniso lide nasal spray and tcrfcnad inc tablets in hay fever. British Jo urna l of Clinical Practice 38: 416-422, 1984 Doherty V, Sylvester DOH . Kenn ed y eTC, Harvey SG. Calthrop

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JG, et al. T reat ment of itching in ato pic eczema with anti histam ines with a low sedative profile. British Medical Journal 298: 96. 1989 Dun can JS. Kenn edy HJ, Triger DR. Treat ment of prur itus du e to chro nic obstru ctive liver d isease. British Medical Journal 298: 22. 1984 Ferguson J. MacDonald KJS. Kenicer KJA. Terfenad ine and placebo compared in the treatm ent of chronic idiopathic urticar ia: a rand omi sed do uble-blind study. British Journ al of Clinical Pharm acology 20: 639-641, 1985 Fink M, Irwin P. CNS effects of the ant ihistam ines diph enh ydram ine and terfenadin e (RMI 9918). Pharmakopsychiatria Neuro psycho phar ma kologie 12: 35-44. 1979 Fredr iksson T. Hersle K. Hjorth N. Mobacken H. Persson T. et al. Terfenadin e in chronic urticaria: a comp arison with clemast ine and placebo . Cutis 38: 128-130, 1986 Fuentes Go nzalez VM. Andrade Garcia JL. Perez Mart in J, Ortega HG . Terfenadine in allergic rhinitis in childr en - preliminary report. Allergia 28: 13-22. 1981 Gaffey MJ. Kaiser DL. Hayden FG. Ineffectiveness of oral terfenad ine in nat ural colds: evide nce against histam ine as a mediator of co mmo n cold sym ptoms. Pediat ric Infectiou s Disease Jo urnal 7: 223-228. 1988 Gai llard AWK. Gruisen A. de Jong R. The influence of antihistami nes on hum an performance. European Journ al of Clinical Pharmac ology 35: 249-253, 1988 Ga rteiz DA. Hook RH, Walker BJ. Okerholm RA. Pharmacokinetics and biotra nsformatio n stud ies of terfenad ine in man. Arzneimittel-Fo rschung 32: 1185-1190, 1982 Gas tpa r H. Dieter ich HA. Compara tive study of the efficacy and tolerance of terfenadine and c1emasti ne in patients with seasonal allergic rh initis. Arzneimittel-Forschung 32: 1211-1213. 1982 Gast par H. Filipp G. Ge issler H. Chabot J. Terfenadine and c1emastine in the treatm ent of acute pollenotic rhini tis. Acta Oto Laryngologica 449: 235-240, 1988 Girard JP . Sommacal-Schopf D. Bigliardi P. Henauer SA. Doubleblind co mparison of astemizo le. terfenad ine and placebo in hay fever with special regard to onset of action. Journ al of Internati on al Medical Research 13: 102-108. 1985 Go MJTh . Wuite J. Arendt C, Bernheim J. Doubl e-blind . placebo contro lled comp ari son of cetirizine and terfenadine in chron ic idiopathic urt icar ia. Acta Therapeutica 15: 77-86. 1989 Grant J A. Bern stein Dl, Buckley CE, Chu T, Fox RW, et al. Double-blind comparison of terfenadme , chlorpheniramine, and placebo in the treatment of chronic idiopathic urticaria . Journal of Allergy and Clinical Immunology 81: 574-579. 1988 Grillage MG. Harcup JW . Mayhew SR, Huddl estone L. Astemizole suspension in the ma intenanc e treatment of paediatri c hay fever: a co mparison with terfenad ine suspensio n. Pharmath erapeu tica 4: 642-647. 1986 G uill MF. Buckley RH. Rocha Jr W. Kemp J P, Segal AT. et al. Multicenter, do uble-blind. placebo-controlled trial of terfenad ine suspensio n in the treatm ent of fall-allergic rhinitis in children. Journ al of Allergy and Clinical Immunology 78: 4-9. 1986 G utkowski A. Bedard P. Del Carp io J. Hebert J, Prevost M. et al. Compa rison of the efficacy and safety of loratad ine. terfenadi ne, and placebo in the treatmen t of seasonal allergic rhinitis. Journ al of Allergy and Clinica l Immunology 81: 902-907, 1988 G utkowski A. Del Car pio J. Gelina s B. Schulz J. Turenn e Y. Com parative study of the efficacy. tolerance and side-effects of dexchlorpheniram ine maleate 6mg bid with terfenadine 60mg

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Larrey D. Palazzo L. Benham ou J-P. Terfenadin e and hepat itis. Annals of Internal Medicine 103: 634. 1985 Leeson GA. Chan KY. Knapp WC, Biedenb ach SA. Wright GJ . et al. Metabolic disposition of terfenadine in laboratory an imals. Arzneimittel-Forschung 32: 1173-1178.1 982 Lindsay-Miller ACM. Chambers A. Group comparative trial of cromolyn sodium and terfenad ine in the treatm ent of seaso nal allergic rh initis. Annals of Allergy 58: 28-32. 1987 Lockhart JD F. Maneksha S. Children with allergies. Terfenad ine suspension versus placebo. Practition er 227: 1313-1315. 1983 Luscom be DK. Nicholls PJ. Parish PA. Co mparison of the effects of azatad ine maleate and terfenadin e on human performa nce. Pharm atherapeutica 3: 370-375. 1983 MacFarlan e PI. Heaf DP. Selective histamine blockade in childhood asthma : the effect of terfenadine on resting bronch ial tone and exercise induced bronchospasm (EIB). Th orax 42: 745. 1987 Makin o S. Ikemo ri R. Fukuda T. Kabe J. Kudo K. et al. Determinati on of the optim um dose of terfenadin e in bronchial asthm a. An open dose-rand omised parallel group multi-centre study. Rinsho Iyaku 4: 687-712. 1988a Mak ino S. Ikem ori R. Fukud a T. Miyamoto T. Suzuki S. et al. Clinica l evaluatio n of terfenad ine in bronch ial asthma - comparison with ketot ifen in a mult i-centre double-blind study. Rinsho Iyaku 4: 1687-1722. 1988b Malet I. Casaj uana A. Ruiz de Leon J. Valero Santiago A. Sanosa Valls J. Za morana Caldero n M. et al. In vivo and in vitro eva luat ion of 4 ant ihistam ines (astem izole. azatadi ne, mequitazine, terfenadine). Allergologia et Immunopathologia 17: 8593. 1989 Meador KJ. Loring DW. Differential cognitiv e effects of terfenadine and chlorpheniramine. Abstract. Proceedings of the AAAI meeting. Anahe im. March 11-16. 1988 Meyer RL. Garten J. Experiences with an expanded test during outpatient therapy with Teld ane in Switzerland . Swiss Medicine 4: 52-54. 1982 Molkh ou P. Beaumont D. Efficacy and toleran ce of terfenadin e suspension in children with allergic rhinitis . Acta Therapeutica II : 99-107. 1985 Moser L. Hiith er KJ. Koch-W eser J. Lundt PV. Effects of terfenadine and diphenh ydram ine alone or in combination with diazepam or alcohol on psychomotor perform ance and subjective feelings. European Journal of Clinical Pharmacology 14: 417-423. 1978 Moskowitz H. Burns M. Effects of terfenadine. diphenh ydramine. and placebo on skills performance . Cutis 42: 14-16. 1988 Murphy-O'Connor JC, Rent on RL. Westlake DM. Comparative trial of two dose regimens of terfenadine in patients with hay fever. Journal of Internat ional Medical Research 12: 333-337. 1984 Neum ann vo n Y. Antihista mine treatment of chronic urt icar ia: result s of a mult icentre trial with azatadin e and terfenadine. Fortschritte der Medizin 102: 967-970. 1984 Nicholson AN. Stone BM. Performance studi es with the H I-histami ne receptor antagonists. astemizo1eand terfenad ine. British Journ al of Clinical Pharmacology 13: 199-202. 1982 Nie megeers G E. Awouters FHL. Jans sen PAJ. Th e in vivo pharmacological profile of histam ine (H tl antagonists in the rat. Drug Developm ent Research 2: 559-566. 1982 O'Hanlon JF . Antihi stam ines and driving safety. Cutis 42: 10-13. 1988 Okerholm RA. Weiner DL. Hook RH. Walker BJ, Leeson GA. et al. Bioavailability of terfenadine in man . Biopharmaceutics and Drug Disposition 2: 185-190. 1981 Orm erod AD, Bake r R. Watt J. Wh ite MI. Terfenadi ne and


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Woodward JK. Munro NL. Terfcnadine, the first non-sedating antihistamine. Arzneimittcl-Forschung 32: 1154-1156. 1982 Wuthrich B. Gulling M. Jundt Th . Comparison of tcrfenadine suspension versus ketotifen syrup in children with atopic dermatitis. A double-blind study . Annual Meeting of European Academy of Allergology and Clinical Immunology. Brussels. 16-19 May. 1984 Yamate M. Biederman AA. Wolfe JD. Goldsobel AB. Chu TJ .

Comparison ofterfenadine in two dosage regimens in the treatment of seasonal allergic rhinitis. Abstract. Journal of Allergy and Clinical Immunology 81: 228. 1988 Authors' address: Donna McTavish. ADIS Press Limited . Private Bag. 41 Centorian Drive . Mairangi Bay. Auckland 10 (New Zealand) .

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Budesonide. An updated review of its pharmacological properties, and therapeutic efficacy in asthma and rhinitis.

Buprenorphine: a review of its pharmacological properties and therapeutic efficacy.

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Mexiletine: a review of its pharmacological properties and therapeutic efficacy in arrhythmias.

Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity.

Nimodipine. A review of its pharmacological properties, and therapeutic efficacy in cerebral disorders.

Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Ramipril. A review of its pharmacological properties and therapeutic efficacy in cardiovascular disorders.

Dextranomer: a review of its general properties and therapeutic efficacy.

Granisetron. A review of its pharmacological properties and therapeutic use as an antiemetic.