Clinical Drug Investigation 22

Clin Drug Invest 2002; 22 (4): 209-220 REVIEW ARTICLE 1173-2563/02/0004-0209/$25.00/0 This material© Adis International Limited. All rights reserved. Therapeutic Use of Levocloperastine as anis Antitussive copyright Agent An Overview of Preclinical Data and Clinical Trials in Adults and Children

P. A l i p r a n d i , 1 L. Cima2 and M. Carrara2 1 Divisionthe of Pneumatology, Rho Hospital, original Rho, Italy 2 Department of Pharmacology and Anaesthesiology, University of Padua, Padua, Italy

Abstract Cough associated with acute and chronic respiratory conditions is common in publisherpatients of all ages. Levocloperastine is a novel antitussive with a pharmacological profile distinct from that of the racemic DL-cloperastine. Levocloperastine with its dual mechanism of action acts on both the central bulbar cough centre and on peripheral receptors in the tracheobronchial tree. In preclinical studies, levocloperastine demonstrated antitussive effects similar to those observed with codeine. In acute and repeated-dose toxicity studies, levocloperastine was well tolerated in rodents and dogs, with no clinically significant cardiovascular or gastrointestinal adverse events. The pharmacokinetic behaviour of levocloperastine, best described by a two-compartmental model with absorption phase, is similar to that of the racemic compound DL-cloperastine. In clinical trials, levocloperastine had a faster onset of action and produced greater reductions in the intensity and frequency of cough compared with DL-cloperastine, codeine Unauthorisedand levodropropizine. The antitussive effects (reduction in intensity and frequency of cough) of levocloperastine were observed after the first day of treatment in patients of all ages. In children, levocloperastine reduced night-time awakenings and irritability; in adults, it was also effective in treating ACE- inhibitor cough. Levocloperastine was generally well tolerated. There was no evidence of clinically significant central adverse events, whereas drowsiness, dry mouth and nausea were reported with comparator agents (levodropropizine, copyingcodeine, DL-cloperastine). Levocloperastine and represents an effective alternative to currently used antitussive agents with the added advantage of faster onset of action and improved tolerability in all patient groups. distribution is Cough, a reflex phenomenon occurring when a number of functions, including acting as an indi- sensitive receptors located in the larynx and upper cator of an underlying illness and as an important airways are activated, is one of the most common defence mechanism to clear the airways. If it symptoms for which patients consult primary care becomes ineffective, excessive or persistent it can physicians andprohibited pneumologists.[1] Coughing serves profoundly and adversely affect a patient’s quality 210 Aliprandi et al. of life.This[2] Treatment of cough depends material on the levocloperastine, DL-cloperastine and dextro- function the cough is serving. When cough indi- cloperastine were similar in the citric acid-induced cates an underlying illness, the aim of therapy is to cough model, suggesting that the antitussive effi- cure such illness, but treatment should also attempt cacy of cloperastine compounds is independent of to control, prevent or eliminate cough using anti- their enantiomeric structure.[4,5] Levocloperastine tussive agents.[3] (as well as dextrocloperastine and DL-cloperast- Levocloperastineis (Privituss®; copyright1 Aesculapius ine) exhibited spasmolytic activity in guinea-pigs Farmaceutici), the levorotatory isomer of DL- via its antihistamine properties in vitro (inhibition cloperastine, is a centrally active, non-opioid anti- of histamine-induced contraction in isolated tussive agent with a chemical structure and tracheal rings) and in vivo (dose-dependent inhibi- pharmacological profile distinct from that of the tion of bronchospasm induced by histamine aero- racemate.the It is devoid of central antinociceptive originalsol).[10] Similarly, serotonin-antagonist activity activities, does not cause addiction or dependence was demonstrated in vitro.[10] Unlike opioid anti- phenomena, and does not interfere with cardio- tussives, such as codeine, the CNS activity of [4,5] vascular or gastrointestinal functions. The levocloperastine is highly selective for the cough therapeutic efficacy of DL-cloperastine in reduc- centre, thus avoiding central adverse effects such ing the intensity and frequency of cough is well as sedation. This attenuation of CNS adverse effects established, with efficacypublisher similar to that of codeine is a differential feature of levocloperastine and is [6-9] and superior to that of dextromethorphan. In related to its specific stereoisomeric properties, this overview, we examine the pharmacological since dextrocloperastine and DL-cloperastine, profile of levocloperastine and its clinical efficacy administered orally or intraperitoneally, induced and tolerability in the treatment of cough asso- sedative and stimulant effects of much greater ciated with a range of respiratory conditions in magnitude (by approximately 50%) in tests of CNS patients of all ages. function in rodents. Levocloperastine, at doses up to 450-fold higher than the therapeutic dose, did 1. Pharmacodynamic Properties not induce any clinically relevant sedation, showing a different pharmacological behaviour from As demonstrated in a number of animal models, that of antihistamine compounds (such as diphen- levocloperastineUnauthorised acts at the CNS level by inhibiting hydramine), despite similarities in chemical struc- [10] the bulbar cough centre. In addition to this ture.[10] There is no strict correlation between seda- primary mechanism of action, peripheral effects tion and H1 antagonist activity, as exemplified by related to its antihistamine, antiserotonergic and second-generation (nonsedating) H1 antagonists muscle-relaxant properties also contribute to the (e.g. terfenadine, astemizole and loratadine), overall efficacycopying of levocloperastine in the treat- which do and not cross the blood-brain barrier appre- ment of cough, bronchospasm and related symp- ciably when given at therapeutic doses. Sedative toms. Administration of levocloperastine 1 to 9 effects of levocloperastine were observed, to a mg/kg to guinea pigs dose-dependently inhibited limited extent, in one test, where orally adminis- cough induced by citric acid or ammonia vapour, tered levocloperastine 10 to 100 mg/kg prolonged showing an antitussive effect similar to that of barbiturate-induced narcosis in mice, although codeine. The 50% effective dose (ED ) values for distribution50 motor performance and is exploratory behaviour levocloperastine vs codeine were, respectively, 2.6 remained unaffected. Only at very high doses vs 3.6 mg/kg in the citric acid test, and 2.9 vs 3.1 (200 to 300 mg/kg) did levocloperastine display mg/kg in the ammonia test. Activities of CNS stimulant and proconvulsant activities, with 1 Use of tradenames is for product identification only and dose-dependent inhibition of barbiturate-induced does not imply endorsement.prohibitednarcosis and enhancement of pentetrazol-induced

TableThis I. Pharmacokinetics of levocloperastine, dextrocloperastine material and DL-cloperastine Parameter and unit Levocloperastine Dextrocloperastine DL-Cloperastine

Cmax ( µg/L) 55.2 68.0 57.2

tmax (min) 90 90 90 Half-life (min) 106 99 112 AUC (µg•min/L) 10 611 10 326 10 919 MRT (min)is copyright 198 192 208 Total clearance (L/min) 0.94 0.97 0.92 Volume of distribution (L/kg) 145 138 148 Volume of distribution at steady state (L/kg) 187 194 194

AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; MRT = mean residence time; tmax =timetoCthemax. original seizures in mice.[10] Levocloperastine did not levocloperastine during pregnancy and breastfeed- affect blood pressure, ECG or heart rate in an- ing is contraindicated because of its ability to cross aesthetised rabbits after intraduodenal administra- the placental barrier.[10] tion of 250 mg/kg,publisher nor did it interfere with gastric emptying or intestinal motility in rats after oral 2. Pharmacokinetic Profile administration of 150 mg/kg.[10] Both acute and repeated-dose toxicity studies found levocloperastine to be well tolerated in Animal studies show that the pharmacokinetic profile of levocloperastine is comparable to that of rodents and dogs. The 50% lethal dose (LD50) value of levocloperastine could not be calculated dextrocloperastine and the racemic compound (table I). After oral administration, levocloperast- because the oral/intraperitoneal doses tested (up to ine is absorbed from the intestine, undergoes first- 2000 mg/kg) did not cause death in any of the pass metabolism and reaches peak plasma concen- experimental animals. By comparison, the enantio- trations (C ) approximately 90 to 120 minutes mer dextrocloperastine was more toxic, with LD max 50 after administration. The pharmacokinetics of valuesUnauthorised of 466 mg/kg in the mouse and 1226 mg/kg levocloperastine are linear over a wide range of in the rat after oral administration, and 155 and doses in the rat (10 to 30 mg/kg) and in the dog 177 mg/kg, respectively, after intraperitoneal (25 to 75 mg/kg), with dose-dependent increases administration. In chronic toxicity studies, of Cmax and AUC and without concomitant changes levocloperastine at dosages up to 75 mg/kg/day in elimination half-life. At very high dosages, such (correspondingcopying to 45 times the therapeutic daily as those and used during chronic toxicity studies in dosage in humans) for 6 months was considered dogs (250 mg/kg), the Cmax was lower than that ‘safe’ in rats and dogs. Mild adverse events predicted by a linear pharmacokinetic model, (including vomiting, anorexia and transient bio- suggesting a saturation process for the absorption, chemical/histological signs of liver and kidney but not excretion, since plasma clearance remained dysfunction) were observed only with dosages of unaltered. Oral bioavailability was >40% based on 250distribution mg/kg/day following 6 months’ treatment. is the ratio of area under the plasma concentration- Levocloperastine did not show mutagenic or carci- time curve (AUC) of unmodified drug calculated nogenic effects in specific in vitro and in vivo stud- after oral and intravenous administration, while ies. Although there is no evidence from animal substantially higher values were obtained in excre- studies of untoward effects on reproductive function studies conducted with radiolabelling tech- tion or embryo/fetalprohibited toxicity, the administration of niques (14C).[11]

LevocloperastineThis undergoes extensive material biotrans- actual bioavailability was not measured) and were formation and is widely distributed throughout thus probably overestimations.[10] the body, with apparent volumes of distribution of 80 L/kg and 150 L/kg after intravenous and oral 2.1 Dose-Ranging Studies administration, respectively. In target organs, particularly in the lungs, it reaches concentrations that The dose-effect relationship of levocloperastine is copyrightwas evaluated in a sequential study conducted in are always higher than those in plasma. In vitro studies show a 1 : 1 blood to plasma ratio, with 40 male patients (mean age 70 years) who had over 97% of the fraction present in the plasma be- cough associated with chronic obstructive pulmo- [10] ing protein bound. Levocloperastine can cross the nary disease (COPD). Patients received three placental barrier (although to a moderate extent), consecutive treatment cycles, lasting 6 days each, but there isthe no evidence of accumulation original (as shown with increasing dosages of levocloperastine (30, 60 in repeated-dose toxicity studies in dogs and rats), and 120 mg/day). Levocloperastine was adminis- and is eliminated in the form of metabolites mainly tered as an oral suspension (2.5, 5 and 7.5ml three in the faeces (two-thirds) and to a lesser degree in times daily). Although all three dosages improved the urine (one-third).[4,5,10] cough and other symptoms of respiratory dysfunc- The pharmacokinetic behaviour of levoclo- tion (with statistically significant differences from publisherbaseline), only doses ≥60 mg/day did so at a perastine observed in animal studies has been clinically relevant level. The 120 mg/day dosage confirmed in human studies. The pharmacokinetics was associated with further improvements in of levocloperastine and racemic DL-cloperastine some respiratory parameters; however, these may were comparable in a single-dose, crossover study be only partially attributable to antitussive therapy in 12 healthy volunteers (six males and six females). (table II). Whereas the two lower dosages were After administration of 10ml of oral suspension well tolerated and did not cause any adverse events containing levocloperastine fendizoate 70.8mg possibly related to the study drug, 12 patients in the (corresponding to 40mg of the chlorhydrate salt 120 mg/day group experienced adverse events, and 36mg of the active principle) or the same including excitatory phenomena. The dosage of amount of racemic levocloperastine, peak plasma 120 mg/day was considered, therefore, too high for µ concentrations of 10 g/L were reached 2 to 4 the therapeutic range. hoursUnauthorised after administration, with a lag-time of approximately 45 minutes before detection of the 3. Clinical Efficacy drug in the bloodstream, suggesting a gradual and protracted absorption from the intestine. A two- The efficacy of levocloperastine was studied in compartmental model with absorption phase, cor- 10 (nine controlled, one non-blind), trials involv- respondingcopying to a tri-exponential concentration-time ing 794 and adults and children (table III). In the nine profile, best describes the pharmacokinetics of controlled studies the effects of oral levocloperast- levocloperastine. The half-lives of levocloperastine were compared with those of placebo, codeine, ine and DL-cloperastine were, respectively, 0.80 DL-cloperastine and levodropropizine. The major- and 0.86h (distribution half-life), 1.68 and 2.16h ity of children enrolled had cough associated with (elimination half-life), and 6.58 and 6.95h (termi- acute bronchial inflammatory conditions, while in naldistribution elimination half-life). The volumes of distribu- is adult/elderly subjects cough was caused by chronic tion (Vd) were 80 ml/kg (terminal) and 57 ml/kg bronchopulmonary disorders. The wide range of (at steady state), and the protein-bound fraction respiratory diseases observed in these patients was high. Total body clearance was 7.5 L/h. It provides a representative sample of those com- should be noted, however, that these data were cal- monly encountered in subjects presenting with culated from theprohibited drug dose administered (as the cough.

TableThis II. Changes in cough-related symptoms following material treatment with levocloperastine 30, 60 and 120 mg/day for 6 days in patients with chronic obstructive pulmonary disease (n = 40). Improvements in cough symptoms are defined as a reduction in point score by one or more points Symptom Baseline 30 mg/day 60 mg/day 120 mg/day Cough intensity (score)a 2.600 ± 0.078 1.575 ± 0.094 0.125 ± 0.082* 0.050 ± 0.050 Cough frequencya 3.100 ± 0.112 2.100 ± 0.106 0.125 ± 0.082* 0.050 ± 0.050 Expectorationisb copyright3.575 ± 0.205 2.650 ± 0.158 0.425 ± 0.129* 0.175 ± 0.107** Dyspnoeaa 1.725 ± 0.080 1.250 ± 0.100 0.375 ± 0.078* 0.250 ± 0.078 Night-time awakenings (no.)c 4.700 ± 0.148 3.100 ± 0.142 0.150 ± 0.084* 0.050 ± 0.050** Auscultatory findings 2.175 ± 0.071 1.700 ± 0.073 0.750 ± 0.086* 0.575 ± 0.087** Fever (no/yes) 20/20 21/19 36/4* 40/0** a Cough symptoms evaluated using a five-point scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, 4 = severe. b 1 = clear sputum,the 2 = sputum containing some original mucus, 3 = mucus, 4 = mucopurulent sputum, 5 = purulent sputum. c Night-time awakenings evaluated on a 5-point scale: 0 = none, 1 = minimal, 2 = infrequent, 3 = frequent, 4 = numerous. *p<0.05vs levocloperastine 30 mg/day; ** p < 0.05 vs levocloperastine 60 mg/day.

3.1 Efficacy MeasurementspublisherSystemic and local tolerability in adults and children were determined by clinical observations and The following efficacy measures were em- laboratory determinations. ployed in the studies described in the following sections. Improvements in subjective, objective (fre- 3.2 Comparative Studies in Children quency and intensity of cough, night-time distur- In two randomised comparative trials in 160 bances, difficulties in expectoration) and labora- children,[12,13] both levocloperastine and levo- tory (respiratory/cardiovascular) parameters were dropropizine improved clinical symptoms com- determined before, during and 5 days after the end pared with baseline values. Overall, there was a of treatment. Frequency and intensity of cough, trend towards more rapid improvements in patients night-timeUnauthorised disturbances, difficulties in expectoration, disruptions in sleep pattern and irritability receiving levocloperastine, with significant re- were evaluated using a five-point scale (0 = absent, ductions in the intensity and frequency of cough 1 = minimal, 2 = moderate, 3 = intense, 4 = severe). observed on days 2 and 5, and day 5, respectively. Improvements were defined as a reduction in point Importantly, levocloperastine reduced the intensity score bycopying one or more points. Expectoration was like- of cough, and reduced night-time awakenings and im- wise determined using a five-point scale (1 = clear proved sleep patterns, with a subsequent reduction sputum, 2 = sputum containing some mucus, in irritability (figure 1). Combined results of both 3 = mucus, 4 = mucopurulent sputum, 5 = purulent studies showed that 77% of patients treated with sputum). Improvements were defined as a reduc- levocloperastine had significant reductions in tion in point score by one or more points. cough intensity after the first day of treatment; distributionFor each patient, investigators rated the re- by day 2, cough frequency iswas reduced in 88% and sponse to therapy as ‘excellent’, ‘good’, ‘fairly irritability was decreased in 92%. Although reduc- good’ or ‘poor’. In general, the antitussive effect tions in irritability were not significantly different was evaluated after 1 day of treatment to minimise between the two treatments, they were consistently interference from spontaneous disease evolution higher in patients receiving levocloperastine and concomitantprohibited therapy and at the end of therapy. compared with levodropropizine.

TableThis III. Overview of clinical trials with levocloperastine material in children and adults Study design Patients Inclusion criteria Duration of Dosage of Dosage of Reference [age (years)] treatment levocloperastine comparator (days) Controlled: 80 [2-13]; Cough associated with: 8-10 8mg bid <4 years; 15mg tid <4 years; Gelsomini[12] levocloperastine vs 45 male, influenza, bronchitis, 12mg bid 4-7 years; 30mg tid 4-7 years; levodropropizine 35 female bronchial asthma, 20mg bid >7 years 45mg tid >7 years is copyrighttracheobronchitis, pharyngonasal-tracheitis, pneumonia

Controlled: 80 [2-11]; Cough associated with: 6-8 8mg bid <4 years; 15mg tid <4 years; Belloni[13] levocloperastine vs 45 male, influenza, bronchitis, 12mg bid 4-7 years; 30mg tid 4-7 years; levodropropizinethe35 female bronchial original asthma, 20mg bid >7 years 45mg tid >7 years tracheobronchitis, pharyngonasal-tracheitis, pneumonia

Non-blind: 144 [34-89]; Cough associated with 15-21 20mg tid Fedeli[14] levocloperastine 90 male, subacute/chronic 54publisher female respiratory conditions

Controlled: 40 [52-89]; Cough associated with 5 20mg tid 20mg tid Traisci[15] levocloperastine vs 20 male, COPD placebo 20 female

Controlled: 50 [22-85]; Cough associated with: 7-12 20mg tid 60mg tid Satta[16] levocloperastine vs 30 male, COPD, chronic bronchitis, levodropropizine 20 female bronchial asthma, pneumonia

Controlled: 60 [28-88]; Cough associated with: 7-11 20mg tid 60mg tid Cassani[17] levocloperastine vs 39 male, COPD, chronic bronchitis, levodropropizineUnauthorised21 female bronchial asthma, pneumonia

Controlled: 40 [43-75]; Cough associated with: 8-10 20mg tid 60mg tid Greco[18] levocloperastine vs 30 male, COPD, chronic bronchitis, levodropropizine 10 female emphysema, copyingbronchopneumonia and Controlled: 60 [56-79]; Cough associated with: 7-13 20mg tid 30mg bid Rossi[19] levocloperastine vs 34 male, COPD, chronic bronchitis codeine 26 female

Controlled: 120 [17-79]; Cough associated with: 9-20 20mg tid 30mg bid Atzeni[20] levocloperastine vs 109 male, COPD, chronic/acute codeinedistribution11 female bronchitis, asthma is

Controlled: 120 [20-90]; Cough secondary to: 13-20 20mg tid 20mg tid Sechi[21] levocloperastine vs 44 male, ACE inhibitors, respiratory DL-cloperastine 76 female conditions bid = twice daily; COPDprohibited= chronic obstructive pulmonary disease; tid = three times daily.

intensity and frequency, night-time awakenings, ThisLevocloperastine material (n = 40) Levodropropizine (n = 40) dyspnoea and expectoration compared with base- 100 95.0 line, with no clinically significant adverse effects 82.5 [15] 78 on respiratory or cardiological function (table V). 80 When associated with COPD, cough is particularly 60 55 difficult to treat and seldom resolves spontan- is copyrighteously; hence, the clinical improvements observed 40

Patients (%) Patients were considered by the investigators to be prob- 20 ably related to treatment.

0 Intensity of cough Irritability 3.4 Comparative Trials in Adults with the originalLevocloperastine, Levodropropizine and Codeine Fig. 1. Percentage of children with improvement in cough symptoms following 1 day of treatment with either levocloperastine or levodropropizine. Cough symptoms were evaluated using a five- In three controlled trials comparing levo- point scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, cloperastine with levodropropizine in 150 adults 4 = severe. Improvements in cough symptoms were defined as with cough, levocloperastine rapidly produced a reduction in point score by one or more points.[13] publisherclinically relevant improvements, with reductions in the frequency and intensity of cough by day 2 (figure 2).[16-18] Importantly, levocloperastine improved clinical parameters more rapidly than 3.3 Non-Blind and Placebo-Controlled levodropropizine, with significant reductions in Trials in Adults cough frequency at day 2 and day 5, respectively, Levocloperastine 60 mg/day significantly in levocloperastine-treated patients. Reductions in improved respiratory symptoms (intensity and night-time awakenings also occurred more rapidly frequency of cough, expectoration, dyspnoea, with levocloperastine than levodropropizine. Log- disturbed sleep, auscultatory findings) in a non- rank chi-squared tests confirmed the probability blind trial in 144 patients with cough associated with subacute/chronic respiratory conditions Table IV. Improvements (day 2 vs baseline values) in cough Unauthorised[14] (table IV). Significant improvements in these symptoms following treatment with levocloperastine in 144 adult parameters were observed after the first day of patients with cough associated with subacute/chronic respiratory treatment, with over 90% of patients experiencing conditions. Improvements in cough symptoms are defined as a reduction in point score by one or more points[14] a reduction in cough intensity (reduction in point Cough symptoma Patients (%) with score by one or more points) after 1 day of improvements in cough levocloperastinecopying treatment. Overall, 95.8% of andsymptoms (90% patients responded to therapy: 79.9% (115/144) confidence interval) were judged by the investigators to have had an Cough intensity 93.75 (89.8-97.7) Cough frequency 57.64 (49.6-65.7) excellent response, 16% (23/144) had a good Expectorationb 43.05 (35.0-51.1) response, and 2.7% (4/144) showed a fairly good Dyspnoea 63.19 (55.3-71.1) response, while in the remaining two patients Night-time awakeningsc 66.65 (59.0-74.4) distributionAusculatory findings is 50.00 (41.8-58.2) (1.4%) response was poor. To confirm the effects of levocloperastine observed in this non-blind trial, a Cough symptoms evaluated using a five-point scale: a series of placebo-controlled and comparative 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, 4 = severe. b 1 = clear sputum, 2 = sputum containing some mucus, 3 = mucus, trials was conducted. 4 = mucopurulent sputum, 5 = purulent sputum. In a placebo-controlled trial in 40 patients with c Night-time awakenings evaluated on a 5-point scale: 0 = none, COPD, levocloperastineprohibited rapidly reduced cough 1 = minimal, 2 = infrequent, 3 = frequent, 4 = numerous.

TableThis V. Cough symptoms at baseline and following material 5 days of treatment with levocloperastine or placebo in patients with chronic obstructive pulmonary disease. Improvements in cough symptoms are defined as a reduction in point score by one or more points[15] Symptom Levocloperastine Placebo baseline post-treatment baseline post-treatment Cough intensitya 2.5 0.3 2.4 1.4 Cough frequencya 5.4 0.3 3.1 1.5 Night-time awakenings (no.) 3.7 1.5 5.3 2.5 isb copyright Expectoration 3.7 1.5 3.6 2.4 Dyspnoeaa 1.6 0.4 1.4 0.9 a Cough symptoms evaluated using a five-point scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, 4 = severe. b 1 = clearthe sputum, 2 = sputum containing some original mucus, 3 = mucus, 4 = mucopurulent sputum, 5 = purulent sputum. of greater improvements in cough intensity and fre- conditions, but the more rapid onset of action of quency with levocloperastine compared with levocloperastine may be clinically advantageous. levodropropizine (96.7% vs 43.3%, p < 0.0001 and Similar effects were observed when levo- 83.3% vs 46.7%, p = 0.0029, respectively). cloperastine was compared with codeine in two Changes in other clinical parameters, such as dys- studies in 180 patients with subacute or relapsing publisher [19,20] pnoea and auscultatory findings, depended on the chronic respiratory diseases. Both treatments efficacy of therapy for the underlying clinical con- were effective, without significant between-group differences in the efficacy parameters. A reduction dition, but importantly the unique pharmaco- in the intensity and frequency of cough were dynamic profile of levocloperastine means that observed in 90% and 87% of levocloperastine significant drug-drug interactions did not occur. recipients, respectively, and reductions in cough Overall, clinical outcomes indicated that both intensity were evident after 1 day of treatment. levocloperastine and levodropropizine are effec- Night-time awakenings were reduced in half of tive in reducing cough in patients with respiratory patients treated with levocloperastine, despite the fact that, on entry, disturbed sleep was not reported to be a problem. Similarly, codeine reduced cough UnauthorisedLevocloperastine (n = 20) intensity, frequency and night-time awakenings in Levodropropizine (n = 20) 80%, 77% and 67% of patients, respectively

100 95.0** (figure 3). Overall, levocloperastine and codeine 85** were judged by the investigators to have good/very 80 good clinical efficacy in 90% and 80%, respec- 60 copyingtively. and 40 35 30 The rapid onset of action of levocloperastine

Patients (%) Patients was confirmed in a large-scale comparative trial 20 in 120 patients with cough associated with ACE 0 inhibitor treatment or other respiratory condi- Intensity of cough Cough frequency tions.[21] Although both levocloperastine and DL- distributioncloperastine improved overall is global symptoms, Fig. 2. Percentage of adults with improvement in cough symptoms following 1 day of treatment with either levocloperastine the clinical effects of levocloperastine occurred on or levodropropizine. Cough symptoms were evaluated using average 3 days before those of DL-cloperastine, a five-point scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, 4 = severe. Improvements in cough symptoms were with significant reduction in cough intensity and defined as a reduction in point score by one or more points. frequency noted after the first day of levocloperast- * indicates significantlyprohibited different, p < 0.001.[18] ine treatment (figure 4). Overall, significantly

This material5. Discussion Levocloperastine (n = 30) Codeine (n = 30) Although cough is a defence mechanism to 100 90.0 87 clear the airways, if it becomes excessive or 80 80 77 persistent it may cause hyperventilation which, in 67 combination with reflex cardiovascular changes, 60 is copyright50 can exacerbate the underlying condition. In these 40 situations, the use of antitussive agents is indicated Patients (%) Patients 20 not only to alleviate the cough but also to prevent 0 more serious events occurring. In addition, cough Intensity of Cough Night-time can disturb sleep and cause nausea, vomiting, loss thecough frequency awakenings originalof appetite and irritability, especially in children. Fig. 3. Percentage of patients with improvement in cough symptoms following 1 day of treatment with levocloperastine or codeine. Cough symptoms were evaluated using a five-point scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, Levocloperastine (n = 60) DL-cloperastine (n = 60) 4 = severe. Improvements in cough symptoms were defined as a reduction in point score by one or more points. Night-time 98.3*** awakenings were evaluated on a 5-point scale: 0 = none, 100 publisher[19,20] 1 = minimal, 2 = infrequent, 3 = frequent, 4 = numerous. 80*** 80 61.7 60 38.3 40 Patients (%) Patients more patients treated with levocloperastine were 20 judged by investigators to have had a very 0 good/good response to therapy compared with Intensity of cough Cough frequency those treated with DL-cloperastine (98.3% vs 76.7%, p < 0.05) [figure 5]. Furthermore, in the subgroup of patients with ACE-inhibitor cough, Fig. 4. Percentage of patients with improvement in cough symptoms following 1 day of treatment with levocloperastine or bothUnauthorised levocloperastine and DL-cloperastine re- codeine. Cough symptoms were evaluated using a five-point duced the intensity and frequency of cough, scale: 0 = absent, 1 = minimal, 2 = moderate, 3 = intense, although in patients treated with DL-cloperastine, 4 = severe. Improvements in cough symptoms were defined as a reduction in point score by one or more points.[21] these improvements were preceded by initial increases in both cough frequency and intensity (figure 6). copying100 andLevocloperastine (n = 60) 85.0 DL-cloperastine (n = 60) 4. Tolerability and Safety 80 73.3 In clinical trials, levocloperastine was generally 60 well tolerated, with mild and transient nausea the 40 Patients (%) Patients only adverse event reported. There was no evi- 20 13.3 15.0 8.4 distribution3.3 is1.7 dence of central adverse events with levocloperast- 0 0 ine, whereas levodropropizine, codeine and DL- Very good Good Fairly good Poor cloperastine caused drowsiness in a number of patients (figure 7). No significant changes in labo- Fig. 5. Rating of clinical efficacy of levocloperastine and DL- ratory (respiratory/cardiovascular/haematologi- cloperastine at the end of therapy as assessed by investiga- cal) parametersprohibited were observed. tors.[21]

This materialMuch research has been conducted to identify antitussive agents that combine therapeutic activity a Levocloperastine (n = 60) DL-cloperastine (n = 60) with good tolerability. The most commonly used 3 2.63 antitussive agents, for example, codeine (an opioid), 2.50 2.42 act centrally on the brainstem opioid receptors. Codeine, previously the standard with which other 2 is1.88 copyright 1.58 antitussive agents were compared, causes central

Score adverse events that limit its use in many patients, 1.00 1.00 1 including those with concomitant diseases, the 0.38 elderly and children. Furthermore, data from a placebo-controlled, double-blind, randomised trial 0 the originalshowed that codeine was no more effective than b syrup vehicle in controlling cough in patients with 4 acute viral infection of the upper respiratory [22] 3.13 tract. In recent years, much work has been car- 3 2.75 ried out to identify drugs that act peripherally on 2.58 2.13 the cough receptors, since these compounds might 2 publisher1.92 be expected to lack secondary central adverse Score 1.13 1.25 events. One such agent, levodropropizine (a non- 1 opioid antitussive that appears to modulate cough 0.50 primarily through peripheral mechanisms) has 0 been demonstrated to be relatively effective in Baseline Day 2 Day 5 Final patients with cough associated with certain conditions, for example, bronchitis and asthma, but not [23,24] Fig. 6. Effects of levocloperastine and DL-cloperastine on the in others. frequency (a) and intensity (b) of cough associated with treat- These limitations fuelled the search for new ment with ACE inhibitors. Cough symptoms were evaluated using a five-point scale: 0 = absent, 1 = minimal, 2 = moderate, effective and well-tolerated agents and led to the 3 = intense, 4 = severe. Improvements in cough symptoms were development of levocloperastine. Coughing, definedUnauthorised as a reduction in point score by one or more points.[21] caused by a range of chemical and mechanical stimuli and present in many respiratory diseases,

20 Levocloperastine copying and DL-Cloperastine 18 16 16 16 Levoropropizine 16 Codeine 14 12 11 10 8 7 6 5 5 4 4 4 3

distribution events of adverse No. is 1 2 0 00 0 0 0 Drowsiness Dry mouth Nausea Total

Fig. 7. Incidence and type of adverse events observed in clinical trials with levocloperastine (n = 469) and comparator drugs [codeine (n = 90), levodropropizineprohibited (n = 155) and DL-cloperastine (n = 60)].

 Adis International Limited. All rights reserved. Clin Drug Invest 2002; 22 (4) Levocloperastine in the Treatment of Cough 219 involvesThis a complex reflex arc that originates material in the encing the beneficial effects of underlying treat- stimulation of receptors in the larynx and upper ment. respiratory tract. Rapidly-adapting ‘irritant’recep- The effects of levocloperastine − rapid reduc- tors, distributed primarily in the walls of the larger tions in the frequency and intensity of cough − airways, have been shown to be important in the were also observed in comparative trials with generation of cough.[25,26] Increased impulse activ- levodropropizine, codeine and DL-cloperastine. is copyrightIn general, levocloperastine was judged to have ity of these receptors is conveyed by the afferent limb to the central cough centre. Integration of this improved/comparable efficacy when compared afferent information by a central site(s) results in with levodropropizine, codeine and DL-cloperast- increased neural activity in the efferent pathways ine. Cough associated with ACE inhibitors occurs to both the expiratory musculature and the air- in a substantial number of patients and represents ways.[27] the originala major clinical problem.[28] In the subgroup of pa- Levocloperastine has a dual mechanism of tients with ACE-inhibitor cough, levocloperastine action. It acts both centrally on the cough centre was more effective than DL-cloperastine in reduc- and peripherally in the walls of the larger airways. ing the frequency and intensity of cough, although This dual mechanism of action accounts for its these effects need to be confirmed in clinical trials efficacy in the treatment of cough associated with involving larger numbers of patients. publisherIn general, adverse events with levocloperastine a wide range of chronic and acute conditions in patients of all ages. Compared with racemic were minor and transient. Significantly, no evi- cloperastine, levocloperastine shows equivalent dence of central adverse effects (sedation) was re- overall efficacy but a faster onset of action and a corded with levocloperastine, whereas drowsiness substantial reduction in adverse events both at was reported by a significant number of patients therapeutic dosages (sedation) and in overdose treated with codeine and, to a lesser extent, with (excitement). Pharmacological studies comparing levodropropizine and DL-cloperastine. The good the racemic and levorotatory forms demonstrated tolerability profile of levocloperastine and its lack of drug-drug interactions make it particularly that these substances differ in their capacity to useful in the treatment of patients receiving con- cross the blood-brain barrier and to affect the comitant medications for underlying conditions bulbar cough centre. This factor, combined with (antibacterials, nonsteroidal anti-inflammatories, peripheralUnauthorised inhibition of inflammatory mediators corticosteroids). (histamine, serotonin) and a reduction of bronchospasm (papaverine-like effect), accounts for the improved clinical efficacy of levocloperastine. 6. Conclusion The pharmacological effects of levocloperastine werecopying confirmed in large-scale clinical trials, Studies and undertaken as part of the clinical devel- non-blind or comparative. In the 10 trials reported opment programme for levocloperastine show that here, oral levocloperastine caused a rapid remis- this antitussive agent is effective and well tolerated sion (after the first day of treatment) in cough in the treatment of cough associated with a range symptoms (intensity and frequency of daytime of acute and chronic respiratory tract conditions in cough and disturbed night-time sleep) in all groups patients of all ages. of patients.distribution In children, the improved sleep quality is resulted in a significant reduction in irritability and an overall improvement in their quality of life. Acknowledgements Importantly, in adult patients with COPD, levocloperastine reduced the frequency and intensity of This review was supported by Aesculapius Farmaceutici dry unproductiveprohibited cough without adversely influ- Srl, Italy.

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