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Indication: Overactive bladder
CADTH Common Drug Review
The CADTH Canadian Drug Expert Committee (CDEC) recommends that propiverine hydrochloride be reimbursed for the symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder, if the following condition is met:
Condition:
Propiverine has a Health Canada indication for the symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with OAB. Propiverine is a detrusor relaxant drug with antimuscarinic and calcium-modulating properties. It is available as 30 mg and 45 mg MR capsules for adult use, and as propiverine-pediatric which is available in 5 mg tablets. The Health Canada–approved dose is propiverine MR 30 mg or 45 mg once daily for adults. A standard daily average of 0.8 mg/kg body weight administered in two doses for children with body weight up to 35 kg (achievable with propiverine-pediatric 5 mg tablets); for children or adolescents with a body weight over 35 kg, the maximum recommended dose is 30 mg administered in two daily doses.
CDEC considered the following information prepared by CDR: a systematic review of RCTs of propiverine and propiverine-pediatric, a critique of the manufacturer’s pharmacoeconomic evaluation, and patient group-submitted information about outcomes and issues important to patients with OAB.
One patient group (The Canadian Continence Foundation) responded to the CDR Call for Patient Input. Information was obtained through online surveys, one-on-one telephone interviews, and informal discussions with patients. The following is a summary of key information provided by the patient group:
The CDR systematic review included three randomized, multi-centre, double-blind placebo and/or active controlled trials in adult or pediatric patients with OAB:
Study 659,1 and Study 1300 assessed the non-inferiority of propiverine MR 30 mg once daily to propiverine IR 15 mg twice daily or tolterodine 4 mg once daily, respectively. Study 1169 evaluated the superiority of propiverine-pediatric 5 mg (weight-dependent dose) compared with placebo. The study discontinuation rates ranged from 3.4% to 11.4% across studies.
The included studies were limited by their short duration (four to eight weeks), high placebo response that is characteristic of trials in patients with OAB, and difficulty interpreting the clinical significance of the results. There were no trials available to assess the 45 mg dose of propiverine MR.
Outcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed the following:
The primary outcome in Study 659,1 was the change from baseline in the number of incontinence episodes per 24 hours. In Study 1169 and Study 1300 the primary outcome was the change in the micturition frequency per 24 hours.
All of the included trials reported reductions from baseline in OAB symptoms (incontinence, micturitions, and urgency) for propiverine 30 mg MR, propiverine-pediatric, tolterodine, and the placebo groups.
The mean differences (95% CI) for the change from baseline in the incontinence episodes per 24 hours were reported as follows:
The mean differences (95% CI) for the change from baseline in the micturition frequency per 24 hours were reported as follows:
The mean differences for the change from baseline in the urgency episodes per 24 hours in Study 659,1 were reported as follows:
In Study 659,1, HRQoL was measured using the KHQ. While all treatments groups experienced improvement in total score from baseline to the end of treatment, propiverine MR 30 mg was not statistically significantly different from placebo.
Overall, the incidence of adverse events, serious adverse events, and withdrawal due to adverse events were similar between propiverine MR and tolterodine. The incidence of overall adverse events associated with propiverine MR (34.3%) or propiverine-pediatric (23.0%) was higher than that reported for placebo (20.3% in Study 659,1and 20.2% in Study 1169). The incidence of overall adverse events was similar between propiverine MR (45.1%) and tolterodine (42%) in Study 1300.
The incidence of dry mouth was higher in the propiverine MR (21.7% to 27.7%), propiverine IR 15 mg twice daily (22.8%) and tolterodine 4 mg (26.5%) treatment groups, compared with placebo (6.4%) in the adult population. The incidence of dry mouth was lower in the pediatric population compared with the adult population, though still higher in the propiverine-pediatric group than in the placebo group: 3.4% in the propiverine-pediatric group versus no events in the placebo group.
No increased risk of cardiovascular adverse events was observed for propiverine MR versus propiverine IR or tolterodine in the adult population: palpitation and chest depression were reported in Study 659,1 and Study 1300; the rate of reporting among patients treated with propiverine ranged from 0.3% to 1.2%, while tolterodine was associated with a rate of 2.5%.
The manufacturer submitted a price of $1.39 per 30 mg or 45 mg propiverine MR capsule (30 or 45 mg once daily, $1.39 per day), and of $0.37 per 5 mg IR tablet (10 mg to 30 mg per day in two doses, $0.74 to $2.22 per day).
The manufacturer submitted a cost comparison of propiverine with oxybutynin IR, tolterodine IR and ER, solifenacin, mirabegron, fesoterodine, trospium, and darifenacin for both the adult and pediatric OAB populations over a one-year time horizon, although the pediatric population analysis included only six months of time on therapy. The manufacturer assumed clinical similarity to other anticholinergics in the adult OAB population on the basis of an RCT comparing 30 mg propiverine MR once daily with 15 mg propiverine IR twice daily and placebo, and a noninferiority trial comparing 30 mg propiverine MR with 4 mg tolterodine ER. No clinical comparisons of propiverine MR with other OAB treatments were available. For the pediatric population, the manufacturer assumed clinical similarity on the basis of a propiverine IR placebo-controlled RCT and a retrospective observational cohort study of children with urinary incontinence due to OAB taking propiverine IR or oxybutynin IR tablets.
Key limitations with the manufacturer’s economic submission included substantial uncertainty in the assumption of clinical similarity between propiverine and comparators, particularly in the pediatric population. Also, for the pediatric analysis, the inclusion of only 180 days of therapy over a one-year analysis time frame, the omission of oxybutynin syrup as comparator, and the underestimation of the patient weight and dose distribution likely to be seen in clinical practice were seen as limitations.
CDR reviewers accepted the manufacturer’s conclusion that at an annual cost of $507 per patient, propiverine MR for adults with OAB was more expensive than oxybutynin IR ($107 per patient annually) and trospium (per patient annually $595). Based on CDR reanalyses for the pediatric population, propiverine-pediatric would cost a weighted-average of approximately $540 per patient annually, which was more expensive than oxybutynin IR ($71 per patient annually) and less than trospium ($595 per patient annually). The experts consulted by CDR believed the most relevant comparator for the pediatric population in Canada is oxybutynin syrup, which was not considered by the manufacturer and costs $378 less per patient annually than CDR’s estimate for propiverine-pediatric. The cost of propiverine MR would need to be reduced by 79% to be considered cost-neutral to oxybutynin IR in the adult population, and by 70% to be considered cost-neutral to oxybutynin syrup in the pediatric population.
CDEC Members:
Dr. Lindsay Nicolle (Chair), Dr. James Silvius (Vice-Chair), Dr. Silvia Alessi-Severini, Dr. Ahmed Bayoumi, Dr. Bruce Carleton, Mr. Frank Gavin, Dr. Peter Jamieson, Dr. Anatoly Langer, Mr. Allen Lefebvre, Dr. Kerry Mansell, Dr. Irvin Mayers, Dr. Yvonne Shevchuk, Dr. Adil Virani, and Dr. Harindra Wijeysundera.
March 15, 2017 Meeting:
Regrets: None
Conflicts of Interest: None
About This Document:
CDEC provides formulary reimbursement recommendations or advice to CDR participating drug plans. CDR clinical and pharmacoeconomic reviews are based on published and unpublished information available up to the time that CDEC deliberated on a review and made a recommendation or issued a record of advice. Patient information submitted by Canadian patient groups is included in the CDR reviews and used in the CDEC deliberations.
The manufacturer has reviewed this document and has requested the removal of confidential information. CADTH has redacted the requested confidential information in accordance with the CDR Confidentiality Guidelines.
The CDEC recommendation or record of advice neither takes the place of a medical professional providing care to a particular patient nor is it intended to replace professional advice.
The Canadian Agency for Drugs and Technologies in Health (CADTH) is not legally responsible for any damages arising from the use or misuse of any information contained in or implied by the contents of this document.
The statements, conclusions, and views expressed herein do not necessarily represent the view of Health Canada or any provincial, territorial, or federal government or the manufacturer.
CDEC Meeting — March 15, 2017
Notice of Final Recommendation — April 19, 2017
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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