Efficacy of Levodropropizine in the Pediatric Setting: a Meta-Analysis of Published Studies

Review

Efficacy of levodropropizine in the pediatric setting: a meta-analysis of published studies

Summary Cough in children is among the most common symptoms and may have a deep impact on children’s and parents’ sleep and quality of life, thus often requiring an empiric treatment with antitussive agents. Levodro- propizine is a very well tolerated peripheral drug, while central cough suppressants (opioids and non opioids) may be associated with side effects that limit their use especially in children. After comprehensive literature search, a meta-analysis of 4 clinical studies of levodropropizine vs. control, including a total of 780 patients, was performed with the aim to evaluate the overall comparative efficacy of levodropropizine in the pediatric population. Meta-analysis of all standardized efficacy parameters (cough frequency, severity, and night awakenings) showed a highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p=0.0044). The heterogeneity test for the efficacy outcome was not statistically significant (p=0.0856). Our meta-analysis indicates that levodropropizine is an effective antitussive drug in children, with statistically significant better overall efficacy outcomes vs. central antitussives (codeine, cloperastine, dextromethorphan), in terms of reducing cough intensity, frequency and nocturnal awakenings. These results further reinforce the favorable benefit/risk profile of levodropropizine in the management of cough in the pediatric setting.

De Blasio F, Lanata L, Dicpingaitis PV, et al. Efficacy of levodropropizine in the pediatric setting: a meta-analysis of published studies. Trends Med 2013; 13(1):9-14. ©2013 Pharma Project Group srl. ISSN: 1594-2848

1 Francesco De Blasio , Luigi Introduction Cough resulting from URTI, al- Lanata2, Peter V. Dicpingaitis3, Federico Saibene2, Rossella Cough in children is among the though usually self-limiting Balsamo2, Alessandro Zanasi4 most common problems refer- within 7 to 15 days, may be a 1Respiratory Medicine and Pulmonary red to pediatricians, and occurs distressing symptom that causes Rehabilitation Section, Clinic Center, significant anxiety to parents for Private Hospital, Naples, Italy more frequently in preschool 2Medical Department, Dompé SPA, than in older children1,2. its frequency and severity. Cou- Milan, Italy The etiology and management gh may have a deep impact on 3Department of Medicine, Albert Einstein the sleep of both children and College of Medicine and Montefiore approach for cough in children Medical Center, Bronx, NY, USA differs greatly to that in adults, parents, on the children’s scho- 4Pneumology Unit, University of so the empirical approach com- lastic and sport activities and Bologna, S.Orsola Malpighi Hospital, thus on their quality of life4,5. Bologna, Italy monly used in adults is unsuita- ble for children3. Clinical evalua- Therefore, an empiric treatment tion of cough in children should with antitussive agents is often include an assessment of envi- used in pediatric cough, even Key words: ronmental factors, particularly though the administration of levodropropizine tobacco smoke, parental concer- inappropriate or unnecessary pediatric ns and expectations4. medications for cough may be antitussives 1,6 Most children with acute cough associated with side effects . cough Mainly two classes of antitussi- meta-analysis are likely to have an uncompli- cated viral acute upper respira- ve drugs are available for the treatment of cough in children: Federico Saibene tory tract infection (URTI), but the possibility of a more serious centrally acting (opioids and non Medical Department, opioids) cough suppressants, Dompé SPA, problem, especially aspiration Milan, Italy of foreign material, should and peripherally acting antitus- e-mail: [email protected] always be considered2,4. sives. Codeine, dextromethor-

January 2013 Volume 13 Number 1 Trends in Medicine 9 F. De Blasio, L. Lanata, P.V. Dicpingaitis, et al. phan and cloperastine are A meta-analysis of studies me- zine were performed vs. central among the most common cen- eting eligibility criteria was per- antitussives (Banderali 199513, trally acting agents that are be- formed with the aim to evalua- Kim 200214, and De Blasio lieved to inhibit cough primari- te the overall efficacy of levo- 20127), while one study was per- ly by their effect on the cough dropropizine versus control in formed vs. placebo (Fiocchi center, while levodropropizine is children. Due to the small num- 199115). an orally administered non- ber of clinical trials in the pe- The study of De Blasio et al.7 opioid agent exerting periphe- diatric population and conside- evaluated the use of antitussive ral antitussive action that resul- ring their different clinical en- drugs in 433 children who re- ts from inhibition of the cough dpoints, the efficacy variables of quired medical consultation for reflex at the peripheral nerve the selected studies were stan- acute cough. A subgroup of 161 level (sensory C fibres) with dardized in order to allow com- children received antitussive tre- modulation of sensory neuro- parison of the overall efficacy atment with levodropropizine peptides within the respiratory of levodropropizine versus con- (N = 101) or central cough sup- tract7-9. trol groups. Our meta-analysis pressants (codeine or cloperasti- In recent years, much attention was performed after standardi- ne, N = 60). Both peripheral and has been drawn to the fact that zation on the overall efficacy central antitussives were effec- some antitussive agents com- variables assessed as endpoints tive in reducing the frequency monly used in the pediatric po- in the eligible studies (i.e., reduc- and intensity of cough. Howe- pulation are not supported by tion in cough frequency, cough ver, a significant advantage was adequate efficacy data, especially severity, and night awakenings). observed for levodropropizine in light of potentially associated For each study, original Abso- vs. central drugs in terms of hi- side effects1. Centrally acting lute Mean Delta were calculated gher cough resolution (p = cough suppressants, although as the mean differences betwe- 0.0012) and lower unsuccessful largely used, have no consistent en the baseline and final values treatment. The superiority of evidence of efficacy and there of efficacy parameters in levo- the peripheral antitussive levo- are increasing reports of asso- dropropizine and control dropropizine vs. central drugs in ciation with serious adverse groups, with the respective (ap- terms of cough resolution was events in children3. proximate) standard deviations independent from cough seve- (SD) and the number of cases rity, with statistically significant Methods (N) studied in single treatment difference also in the subgroups groups. Standardized Mean Del- of patients with higher cough A comprehensive systematic li- ta were calculated by means of intensity (moderate and severe). terature search was performed the original Absolute Mean Del- In a double blind randomized on the main electronic databa- ta (with their SD and N) and study carried out by Kim et al.14, ses (PubMed/MEDLINE, represent a fraction or multiple the efficacy of levodropropizi- EMBASE, and Cochrane Li- of unitary standard deviations, ne was compared to the central brary) from their inception expressed as standardized uni- antitussive dextromethorphan throughout January 2012, to ts10-12. in 77 children with bronchitis. identify original clinical studies After 2-3 days of administra- of levodropropizine for the tre- Study Selection tion, both severity and frequen- atment of cough in the pedia- cy of cough were reduced more tric population. A total of 9 published clinical significantly in the levodropro- The inclusion criteria used to studies conducted with levodro- pizine group than in the dextro- select studies were established a propizine in the pediatric setting methorphan group (p = 0.003). priori. Only controlled studies were identified by means of our Also the final efficacy score re- (vs. both active control and pla- systematic literature search, in- sulted significantly higher with cebo) including pediatric patien- volving an overall population of levodropropizine vs. dextro- ts and assessing efficacy en- 1242 children. methorphan (p = 0.003), dpoints related to cough outco- Out of these, 4 studies including showing a more favorable anti- mes were selected for our analy- a total of 780 patients met the tussive effectiveness of levodro- sis. Non controlled studies and eligibility criteria and were se- propizine in comparison to dex- studies evaluating only safety lected for our meta-analysis. tromethorphan. endpoints were excluded. Three studies of levodropropi- Banderali et al.13 evaluated in a

10 Trends in Medicine January 2013 Volume 13 Number 1 Efficacy of levodropropizine in the pediatric setting double blind randomized study antitussive efficacy of levodro- nings) assessed in each of the the efficacy of levodropropizi- propizine vs. control in the pe- eligible clinical studies, both in ne compared to dropropizine in diatric setting are summarized in levodropropizine and control the management of non-pro- Table 1. groups. ductive cough in 258 pediatric Main efficacy outcomes of the The results of the standardiza- patients. The results demonstra- 4 clinical trials included in this tion of different efficacy varia- ted statistically significant decre- meta-analysis were frequency of bles, in order to make the effi- ases in the frequency of cou- cough, severity of cough, and cacy parameters comparable, are ghing spells and nocturnal nocturnal awakenings. also shown in Table 2 as Stan- awakenings with both levodro- Other 5 published open-label dardized Mean Delta (with 95% propizine and dropropizine, uncontrolled studies evaluating C.I. and p values between treat- without significant difference the antitussive effect and tole- ment groups). between treatment groups. rability of levodropropizine in The results of the meta-analy- The efficacy of levodropropizi- children, involving a total of 462 sis of all standardized parame- ne vs. placebo on nocturnal cou- children, were excluded from ters, representing overall antitus- gh was investigated by Fiocchi our analysis according to selec- sive efficacy, showed a highly et al.15 in a small double blind tion criteria16-20. statistically significant differen- randomized study in 12 children ce in efficacy in favor of levo- with asthma. The number of Results dropropizine versus control tre- nocturnal awakenings was signi- atments (including central cou- ficantly reduced with levodro- Table 2 shows the original Ab- gh suppressants), with a p-va- propizine (p = 0.008) but not solute Mean Delta (with SD and lue of 0.0044 (Table 3). with placebo (p = 0.159). N) calculated for each efficacy The size of antitussive effect of The main characteristics of pu- parameter (cough frequency, levodropropizine vs. control tre- blished studies evaluating the cough severity, and night awake- atments in the pediatric setting

Table 1. Clinical Studies of Levodropropizine vs. Control in Children.

Study Sample Size Age Design Condition Results

De Blasio 433 children 1-15 yrs Levodropropizine URTI-related Significantly higher 20127 vs. Cloperastine/ Cough cough resolution Codeine (p=0.0012) and lower unsuccessful treatment with levodropropizine, independently from cough intensity.

Kim 77 children 2-3 yrs Double blind Bronchitis Significantly higher 200214 randomized Cough reduction in cough Levodropropizine severity and frequency vs. with levodropropizine Dextromethorphan (p=0.003).

Banderali 258 children 2-14 yrs Double blind Non-Productive Significant decrease in 199513 randomized Cough cough frequency and Levodropropizine night awakenings with vs. Dropropizine both levodropropizine and dropropizine.

Fiocchi 12 children 2-8 yrs Double blind Asthmatic Significant reduction in 199115 randomized Cough nocturnal awakenings Levodropropizine with levodropropizine vs. Placebo (p=0.008), not with placebo.

January 2013 Volume 13 Number 1 Trends in Medicine 11 F. De Blasio, L. Lanata, P.V. Dicpingaitis, et al.

Table 2. Absolute and Standardized Mean Delta (lLevodropropizine vs. Controls).

Levodropropizine Controls Studies/ Standardized Parameters Absolute SD N Absolute SD N Mean Delta 95% C.I. p Mean Delta Mean Delta Lower Upper

Banderali 19958/ Frequency -8.4 17.3 130 -7.7 13.7 126 -0.045 -0.291 0.202 0.7216 Kim 200214/ Frequency -1.3 1.14 38 -0.7 1.12 37 -0.525 -0.996 -0.055 0.0290 Banderali 19958/ Nocturnal awakenings -1.0 2.55 132 -1 2.46 126 0.000 -0.246 0.246 1.0000 Fiocchi 199115/ Nocturnal awakenings -1.06 0.81 12 -0.46 0.74 12 -0.747 -1.639 0.146 0.0966 Kim 200214/ Severity -1.2 1.0 38 -0.7 0.99 37 -0.495 -0.967 -0.028 0.0391 De Blasio 20127/ Severity -1.58 0.96 101 -1.1 1.13 60 -0.465 -0.792 -0.139 0.0055

Differences indicate improvement in efficacy parameters

is shown in the overall efficacy Discussion and despite some limitations mainly meta-analysis chart (Figure 1). Conclusions linked to the small number of Concerning the estimated effi- trials included in the analysis and cacy outcomes, levodropropizi- Cough is very common in chil- the different efficacy variables ne was superior to controls in dren of all ages and its frequen- assessed, provides an overview all 4 clinical studies, also rea- cy and severity may have a deep of the major comparative evi- ching a statistically significant impact on children’s and paren- dence on levodropropizine in difference (p < 0.05) in 2 stu- ts’ sleep and quality of life, the- terms of efficacy in the pedia- dies1,14. refore often requiring an empi- tric setting. In our meta-analysis, the test of ric treatment with antitussive The results of our meta-analy- heterogeneity for the efficacy agents7. sis indicate that levodropropizi- outcome was not statistically si- This standardized meta-analysis ne is an effective antitussive gnificant (p = 0.0856). of published clinical studies, drug in children, showing stati-

Table 3. Meta-analysis of Overall Antitussive Efficacy (lLevodropropizine vs. Controls).

Levodropropizine Standardized 95% C.I. p vs. Mean Delta Lower Lower Controls -0.205 -0.344 -0.066 0.0044

12 Trends in Medicine January 2013 Volume 13 Number 1 Efficacy of levodropropizine in the pediatric setting

Figure 1. Meta-analysis of the efficacy of levodropropizine vs. controls in pediatric studies.

Banderali (frequency of cough)

Kim Dong Soo (frequency of cough)

Banderali (awakenings)

Fiocchi (awakenings)

Kim Dong Soo (severity of cough)

De Blasio (severity of cough)

Meta-analysis: P=0.004 Heterogenity: P=0.0856 Levodropropizine better Control better

-3 -2 -1 0 1

No difference

stically significant better outco- These positive overall efficacy with serious side effects that mes vs. central antitussive drugs results are particularly impor- limit their use especially in chi- (codeine, cloperastine, dextro- tant considering that levodro- ldren, thus further reinforcing methorphan) in terms of ove- propizine is a very well tolera- the favorable benefit/risk pro- rall efficacy in reducing cough ted peripheral antitussive drug7, file of levodropropizine in the intensity, frequency and night while centrally-acting cough management of pediatric cou- awakenings. suppressants may be associated gh1. TiM

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