2009 THE AUTHORS . JOURNAL COMPILATION 2009 BJU INTERNATIONAL Reconstructive and Paediatric Urology EFFICACY, TOLERABILITY AND SAFETY OF PROPIVERINE VS OXYBUTYNIN IN CHILDREN WITH URGE INCONTINENCE FROM OAB ALLOUSSI ET AL. Efficacy, tolerability and safety of propiverine hydrochloride in comparison to oxybutynin in children with urge incontinence due to overactive bladder: Results of a multicentre observational cohort study BJUIBJU INTERNATIONAL Schahnaz Alloussi, Gerd Mürtz1, Reinhard Braun2, Ulrich Gerhardt2, Martina Heinrich3, Eva Hellmis2, Werner Horn2, Daniela Marschall-Kehrel2, Kurt Niklas2, Michael Raabe2, Thomas Rößler2, Beatrix Seibt2, Stefan Siemer4, Daniela Schultz-Lampel5, Heiko Walter2, Burkhard Wiedeking2, Saladin Alloussi, Paul Bock6, Gerhard Strugala1 and Helmut Madersbacher7 Department of Urology and Paediatric Urology, Krankenhaus Neunkirchen GmbH, 1APOGEPHA Arzneimittel GmbH, Dresden, 2Urological Practice or General Practitioner (Leipzig, Dresden, Duisburg, Mönchengladbach, Stadtlengsfeld, Frankfurt/Main, Saarlouis, Rottweil, Zwickau, Grimmen and Essen), 3Dr von Haunersches Kinderspital, Kinderchirurgische Klinik, 4Department of Urology, University of Saarland, Homburg/Saar, 5Kontinenzzentrum Südwest, Klinikum Villingen-Schwenningen, Germany, 6IFAG Basel AG, Switzerland, and 7Department of Neuro- Urology, Landeskrankenhaus-Universitätskliniken-Innsbruck, Innsbruck, Austria Accepted for publication 13 August 2009 adverse events, adverse drug reactions events (3.9% vs 16.3%, odds ratio 4.813), Study Type – Therapy (observational caused by antimuscarinics and premature adverse drug reactions caused by propiverine cohort) treatment termination. or oxybutynin (2.8% vs 9.2%) and premature Level of Evidence 2b treatment termination due to adverse drug RESULTS reactions (1.6% vs 4.4%). OBJECTIVE At 16 study centres, 621 children aged To compare, in a retrospective observational 5–14 years with UI due to overactive bladder CONCLUSION cohort study, the efficacy, tolerability and were enrolled. After anticholinergic safety of propiverine and oxybutynin in treatment (437 propiverine, 184 oxybutynin) Propiverine and oxybutynin are effective in children with urge incontinence (UI) due to continence was achieved in 61.6% and children with UI due to overactive bladder. overactive bladder. 58.7% of the patients after 186 and Sufficient treatment periods of at least 2, 259 days, respectively. There were clinically preferably 3–4, months are the crucial PATIENTS AND METHODS relevant improvements in voiding frequency factors for a successful treatment. The across treatment groups. Daily doses of tolerability profile of propiverine is better Medical records were scrutinized for children propiverine were markedly below the than for oxybutynin. with UI. As a primary efficacy outcome recommendations (0.54 vs 0.8 mg/kg body variable the achievement of continence after weight), daily doses of oxybutynin were treatment with variable doses of propiverine according to the recommendations (0.31 vs KEYWORDS or oxybutynin was assessed. Weekly UI 0.2–0.4 mg/kg body weight) at treatment episodes and daily voiding frequency were initiation. There was a significantly more anticholinergics, children, overactive evaluated as secondary efficacy outcomes. favourable tolerability to propiverine than bladder, oxybutynin, propiverine, urinary Tolerability was evaluated by the rate of oxybutynin for the overall rate of adverse incontinence INTRODUCTION date, oxybutynin, propiverine, tolterodine and studies, despite enrolling many patients [1]. trospium chloride have been investigated, but For trospium chloride only one dose-finding Anticholinergics and behavioural to a very varied extent. Tolterodine was not study has been conducted so far [2]. The use interventions are the mainstays for treating confirmed to be effective in children with OAB of oxybutynin is primarily based on clinical children with an overactive bladder (OAB). To in two multinational, multicentre clinical experience in adults. Controlled clinical © 2009 THE AUTHORS 550 JOURNAL COMPILATION © 2009 BJU INTERNATIONAL | 106, 550–556 | doi:10.1111/j.1464-410X.2009.09129.x EFFICACY, TOLERABILITY AND SAFETY OF PROPIVERINE VS OXYBUTYNIN IN CHILDREN WITH UI FROM OAB studies in children [3] are rare, and clinical responsible for the conduct of the study. oxybutynin (two-sided test, α = 0.05). Based reports consistently show limited tolerability Altogether, 34 of 50 institutions initially on the above defined ‘success’ probabilities of [4]. Even for oxybutynin extended-release responding expressed principal interest in both treatment groups, the one-sided 97.5% only a few open-label trials with few patients study participation, whereof 16 across CI of the OR was calculated. Logistic have been conducted [5]. Nevertheless, Germany invested the required time to regression was used to determine the OR and despite these major disadvantages, participate. At these centres all medical to adjust the endpoint to baseline imbalances oxybutynin remains the most frequently records of children with the indication under and confounders. The critical value for prescribed anticholinergic worldwide in investigation were scrutinized and noninferiority of 14%, based on expert children. A more favourable tolerability chronologically enrolled during the period opinions, assuming a success-probability of and safety profile has been reported for 1998–2003. The following key inclusion 0.5 (50%) for the propiverine treatment, is propiverine [6], a compound with a dual mode criteria had to be fulfilled: (i) Urge equivalent to an OR of 0.563. These analyses of action, with anticholinergic and calcium- incontinence due to OAB in patients of the primary efficacy outcome variable channel-modulating effects [7]. In children, presenting with the core symptoms of urge ‘continence’ were conducted both without propiverine has been extensively investigated, incontinence and urgency. In accordance (unadjusted) and with (adjusted) especially in neurogenic [8–10], but also in with standards given meanwhile by the consideration of confounding variables. non-neurogenic conditions [11,12]. Recently, International Children’s Continence Society Thus the statistical analysis comprised as Marschall-Kehrel et al. [13] reported that in [16] a noninvasive diagnostic approach was a first-step approach the assessment of OAB, propiverine was significantly better than chosen; (ii) patients aged 5–15 years; (iii) oral noninferiority (i.e. clinical equivalence) of placebo, the first study to show the efficacy of anticholinergic treatment with either propiverine compared to oxybutynin. Only if an anticholinergic in children with this propiverine (5 mg, or of higher body weight, there was a significant result was the second- condition. Thus the aim of the present study 15 mg per coated tablet) or oxybutynin (2.5 or step approach planned of superiority (i.e. was to compare the efficacy, tolerability 5 mg tablets). Both drugs were applied as superior clinical efficacy) of propiverine and safety of propiverine and oxybutynin immediate-release formulations in variable compared to oxybutynin. These analyses had in children with urinary incontinence individual doses; (iv) treatment periods of both no adjustment for confounders. due to OAB. ≥3 months incorporating visits not scheduled but conducted according to clinical need. Key As the secondary efficacy outcome the PATIENTS AND METHODS exclusion criteria comprised: (i) children following variables were assessed according presenting with night-time symptoms only, to the data given in the patients’ files: Weekly According to Benson and Hartz [14] in a suggestive of nocturnal enuresis, were not incontinence episodes before and after retrospective cohort study, a representative eligible; (ii) children with a history of treatment; daily voiding frequency before sample of patients with the disease under recurrent chronic or acute UTI at treatment and after treatment; and overall efficacy investigation is chronologically selected from initiation; (iii) residual urine was excluded by assessment of the patients, conducted by the the population, irrespective of the applied ultrasonography; (iv) pathologies of the upper physicians (categories ‘continent’, ‘improved’, treatments and the results achieved. This urinary tract were also excluded. ‘not improved’, and ‘deteriorated’). design analyses anonymously data already Furthermore, continence rates were evaluated present before starting the study, with no This study reflects a ‘real-life’ clinical setting, in relation to the daily doses of propiverine further therapeutic interventions. Neither because the eligibility of patients was neither and oxybutynin, and for treatment duration. votes of ethics committees nor informed restricted for the prescribed doses of consent of the patients are mandatory. anticholinergics nor for concomitant As tolerability and safety variables the medication. Due to the non-interventional incidence rates of patients presenting with The present study was conducted as a character of the study, implying that the spontaneously reported adverse events (AEs), multicentre, comparative parallel-group investigators were responsible for all adverse drug reactions (ADRs) caused by observational cohort study with standardized diagnostic and therapeutic measures, patients propiverine or oxybutynin, its severity data collection, considering methods of Good were not randomly assigned to treatment grading, CNS-related ADRs and premature Epidemiologic Practice [15]. groups.