Regulatory Decision Summary for Mictoryl, Mictoryl Pediatric

The safety and efficacy of the modified release (MR) 30 mg and 45 mg propiverine for adults and the immediate release (IR) 5 mg propiverine for pediatric population in the treatment of over active bladder (OAB) was evaluated from several clinical trials.

Adult population
In general, in the treatment of adult patients with OAB, both 30 mg and 45 mg propiverine MR strengths were statistically significantly superior to placebo in the primary (incontinence episodes, number of micturitions) and many secondary efficacy endpoints (residual volume, volume per micturition). Randomized controlled clinical efficacy studies on OAB adult patients with propiverine MR 30 mg demonstrated comparable efficacy results to tolterodine (4mg extended release formulation) or oxybutynin (5mg immediate release formulation), which are the currently approved products for such condition. Long-term studies on OAB adult patients confirmed that there was no loss of efficacy up to 2 years of propiverine treatment. Elderly patients also benefit from the treatment.

Most adverse drug reactions (ADRs) observed in adult patients with propiverine were those known for the pharmacological class of antimuscarinic drugs. Based on placebo controlled trials, dry mouth was the only very common ADRs (17-29%). Other common ADRs were constipation (3% -6%), eye disorders (1-4%), abdominal pain (0.4-1.8%) and headache (0.1-1.5%). ADRs were usually mild, self-limited and have the tendency to decrease over time. Although ECG recordings were obtained from OAB patients in different studies, a thorough QTc interval study according to ICH E14 guidelines was not performed. However, a search of pharmacovigilance database done by the sponsor did not show any report of QT interval prolongation, cardiac arrest, sudden cardiac death or ventricular fibrillation attributed to propiverine treatment. In addition, the risk of cardiovascular effects including potential QTc interval prolongation has been strengthened in the Product Monograph.

Pediatric population
The efficacy and safety of propiverine IR 5 mg in children with OAB was assessed in large part in a randomized, double-blind, placebo-controlled parallel-group, multicentre, multinational phase III trial for 8 weeks. A total of 164 subjects were included (84 in in the propiverine group and 80 in the placebo group). For the primary efficacy end point, the mean number of micturitions within 24 hours was significantly reduced in the propiverine group compared to the placebo group. Results of secondary end points in this study supported the primary end point. There was also supportive efficacy information from other studies beyond 8 weeks in children with OAB.

Overall, 23.0% patients in the propiverine group and 20.2% patients in the placebo group experienced treatment emergent adverse events (TEAE). The most commonly reported TEAE were infections and infestations (13.8% patients in the propiverine group and 15.5% patients in the placebo group); gastrointestinal disorders (9.2% patients in the propiverine group and 3.6% patients in the placebo group); eye disorders (2.3% patients in the propiverine group only); nervous system disorders (2.3% patients in the propiverine and 1.2% in the placebo group).

In summary, propiverine MR and IR formulations are efficacious in the treatment of OAB in adult and pediatric patients, respectively. Propiverine is relatively well tolerated and most adverse events observed in propiverine treated subjects were those known for the pharmacological class of antimuscarinic drugs. The available clinical efficacy and safety data indicate that the overall Benefit-Harm-Uncertainty assessments support the approval propiverine for adult and pediatric populations with OAB.