Summary Basis of Decision for Mictoryl/Mictoryl Pediatric

Clinical Pharmacology

Propiverine (the medicinal ingredient in Mictoryl/Mictoryl Pediatric) exhibits anticholinergic and calcium-modulating properties. The efferent connection of the pelvic nerve is inhibited due to anticholinergic action resulting in relaxation of bladder smooth muscle and thereby increasing the amount of urine that the bladder can hold. In addition, propiverine inhibits the calcium influx and modulates the intracellular calcium in urinary bladder smooth muscle cells causing musculotropic spasmolysis.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacology studies provided a thorough characterization of the clinical pharmacology of Mictoryl/Mictoryl Pediatric and provided substantive support for labelling claims. Together, the clinical and pharmacological data support the use of Mictoryl/Mictoryl Pediatric for the treatment of overactive bladder (OAB).

For further details, please refer to the Mictoryl/Mictoryl Pediatric Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of 30 mg Mictoryl MR capsules in adult patients with OAB was evaluated primarily based on two randomized controlled clinical studies, P 659-1 and P 1300. Two additional randomized controlled studies (P 997 and P 1320) conducted in patients with neurogenic detrusor overactivity (NDO) was also included as part of the submission. However, during the review process, the proposed NDO indication was withdrawn (see Indication in Clinical Efficacy). As a result, the following discussion on clinical efficacy shall be limited to the clinical studies relevant in support of the approved indication of OAB. The 45 mg Mictoryl MR capsule was verified through a comparative bioavailability study, P 506-1.

The efficacy of 5 mg Mictoryl Pediatric IR in children with OAB was evaluated primarily based on a placebo-controlled Phase III study, P 1169.

Study P 659-1

The efficacy of 30 mg Mictoryl MR was demonstrated in a Phase III/IV double blind, randomized, placebo and active-controlled, parallel group study which compared 30 mg Mictoryl MR to 15 mg propiverine hydrochloride twice daily (BID) (European marketed reference product) or a placebo. A total of 988 patients were enrolled in the study.

The primary efficacy endpoint was the change from baseline in the number of incontinence episodes within 24 hours. The primary efficacy endpoint was evaluated with the hypotheses to test for non-inferiority of 30 mg Mictoryl MR to 15 mg Mictoryl IR, as well as to show superiority of 30 mg Mictoryl MR and 15 mg Mictoryl IR over a placebo.

Secondary efficacy endpoints included number of micturitions and urge episodes in 24 hours, voided volume per single micturition, quality of life (measured by King's Health Questionnaire), and the evaluation of efficacy by patient and investigator.

The study design consisted of a run-in period of 7 days. Patients were then treated for 32 days with either 30 mg Mictoryl MR once daily, 15 mg Mictoryl IR twice daily (BID) or a placebo with randomization in a 2:2:1 ratio, respectively. The study schedule included 4 visits: Visit 1 (Day -7 to -1), Visit 2 (Day 0), Visit 3 (Day 28+3), and Visit 4 (Day 32+3).

Male and female patients aged 18 years or older with symptoms of OAB were included in the study. Main criteria for inclusion were at least two incontinence episodes within three days, and at least 10 micturitions within 24 hours.

Results from the P 659-1 study showed that both 30 mg Mictoryl MR and 15 mg Mictoryl IR (BID) treatments were statistically significantly superior to placebo, thereby supporting the primary efficacy endpoint.

Results of the secondary efficacy endpoints also further supported the primary efficacy endpoint. The number of micturitions and urge episodes within 24 hours was significantly reduced in the Mictoryl MR groups compared to the placebo group, whereas the difference between 30 mg Mictoryl MR and 15 mg Mictoryl IR (BID) was not significant.

The mean volume per single micturition increased significantly more in the Mictoryl IR group than in the placebo group, but the differences between the Mictoryl groups as well as between Mictoryl MR and placebo were not significant.

The quality of life improved more pronouncedly in patients treated with Mictoryl compared to placebo. Furthermore, investigators rated the overall efficacy as moderate, good or very good for most of the patients.

Therefore, from an efficacy point of view, the above study results support the conclusion that 30 mg Mictoryl MR once daily is non-inferior to the established 15 mg Mictoryl IR administered twice daily and that both products are significantly superior when compared to a placebo.

Study P 1300

This double blind, double dummy, randomized, active-controlled, parallel group study evaluated the efficacy of 30 mg Mictoryl MR with that of 4 mg tolterodine extended-release (ER) in 324 patients with OAB who were treated for an 8-week period. The study design was that of a randomized, double-blind, double-dummy, parallel-group, multicentre Phase III study.

The primary efficacy endpoint was the change from baseline in the number of micturitions per 24 hours.

Secondary efficacy endpoints were similar to those specified previously in the P 659-1 study.

The study design consisted of a 2-week wash-out and screening period. Patients then received either 30 mg Mictoryl MR or 4 mg tolterodine ER for 8 weeks. The study schedule consisted of 7 visits: Visit 1 (wash-out/screening, Day -14), Visit 2 (randomization, Day 0), Visit 3 (Day 14 ± 3), Visit 4 (Day 28 ± 3), Visit 5 (Day 42 ± 3), Visit 6 (End of Treatment, Day 56 ± 3), and Visit 7 (follow-up).

Male and female patients aged 18 to 75 years with symptoms of OAB were included in the study. Main criteria for inclusion were symptoms of OAB ≥3 months, average frequency of micturition ≥8/24 hours, urgency with or without urge incontinence episodes during screening, and mean voided volume of single micturition ≤200 mL.

Results from the P 1300 study demonstrated that following 8 weeks of treatment, the mean number of micturitions in a 24-hour period was reduced by 30.2% and 25.7% in the 30 mg Mictoryl MR and 4 mg tolterodine ER group, respectively.

The improvement of all micturition diary parameters after already 2 weeks of treatment demonstrated an early onset of efficacy with further enhancement under prolonged therapy. The statistical analyses showed significant differences between pre- and post-treatment in both groups (p <0.0001). The study demonstrated that 30 mg Mictoryl MR administered once daily over 8 weeks in OAB patients is non-inferior compared to the standard dose of 4 mg tolterodine ER 4 with respect to all relevant micturition diary parameters, and the number of incontinence episodes was more effectively reduced with 30 mg Mictoryl MR (p = 0.0338).

The secondary efficacy endpoints also supported the primary efficacy endpoint. The number of incontinence episodes per 24 hours was significantly reduced for both groups (Mictoryl MR and tolterodine ER) after 2 and 8 weeks of treatment. For Mictoryl MR, the pre-post difference was more reduced compared to the tolterodine ER group (74.6% versus 60.3%).

The mean volume per single micturition increased significantly and with no difference between both substances after 2 and 8 weeks of treatment in the Mictoryl and tolterodine group, respectively.

In summary, Study P 1300 demonstrated that 30 mg Mictoryl MR administered once daily over 8 weeks in OAB patients is non-inferior to the standard dose of 4 mg tolterodine ER with respect to all relevant micturition diary parameters, whereas the number of incontinence episodes was more effectively reduced with 30 mg Mictoryl MR.

Study P 1169

The efficacy of 5 mg Mictoryl Pediatric IR in children with OAB was evaluated primarily in a randomized double-blind, placebo-controlled Phase III study, P 1169. A total of 171 children aged 5 to 10 years were enrolled in this study. The main criteria for inclusion consisted of more than 8 micturitions per 24 hours and at least one incontinence episode within 7 days. Exclusion criteria included an age-expected physiological bladder capacity, nocturnal enuresis, dysfunctional voiding, or neurogenic detrusor overactivity.

The primary efficacy endpoint was the change from baseline in the number of micturitions per 24 hours.

Secondary efficacy endpoints included weekly incontinence episodes; number of incontinence episodes over 3 days; average voided volume per single micturition within 3 days; maximum voided volume determined per weekly micturition protocol; response rates based on change of micturition frequency per 24 hours (decrease by ≥1.5 micturitions); and parents, patients and investigators' evaluation of efficacy.

The study design consisted of a 3-week run-in period where children and parents were informed about the disease pattern and received general life-style advice (urotherapy). Children not responding to these life-style modifications were treated with body weight adjusted doses of 5 mg Mictoryl Pediatric IR (17.0-27.9 kg = 10 mg twice daily [2x IR 5 mg twice daily]; 28.0-45.0 kg = 15 mg twice daily [3xIR 5 mg twice daily]) or corresponding placebo for 8 weeks.

The patient population consisted of 41 (32.3%) females and 86 (67.7%) males. The mean age of the patient population was 6.9 years and mean body mass index was 16.26 kg/m².

Results from the study demonstrated that the primary efficacy endpoint (mean number of micturitions within 24 hours) was statistically significantly reduced from 9 micturitions at baseline to 7 at the end of treatment in the Mictoryl Pediatric group compared to the placebo group (from 9 at baseline to 8 at end of treatment). In addition, results from the secondary endpoints supported the primary endpoint.

One limitation to note in regards to the pediatric study was that the duration of treatment was 8 weeks instead of 12 weeks. Although there was additional supportive information on efficacy beyond 8 weeks in children with OAB, the median treatment duration from the supportive study was approximately 4.1 months. In addition, there was limited efficacy and safety data in children and adolescents of higher body weight (≥35 kg) receiving daily dose of 30 mg Mictoryl Pediatric IR. The Mictoryl/Mictoryl Pediatric Product Monograph clearly highlights these limitations.

Study P 506-1

The development of a second strength, 45 mg Mictoryl MR, was based on the same rationale that there is a relation between the pharmacological/toxicological response and the systemic exposure to the drug metabolites. The aim of the development was to reach a similar total exposure to the drug as that of 15 mg propiverine hydrochloride IR tablet (European marketed reference product).

Study 506-1 assessed the pharmacokinetics of 45 mg Mictoryl MR compared to 15 mg Mictoryl IR (TID) in a randomized, double-blind, double-dummy, multiple-dose, two-period cross-over multiple-dose bioequivalence study. In this study, 28 healthy volunteers received either 45 mg Mictoryl MR capsules once daily or 15 mg Mictoryl IR tablets three-times daily (TID). Treatment was administered for 7 days with a washout period of 14 days between treatments.

Results from this study demonstrated that 45 mg Mictoryl MR exhibited comparable bioavailability to the reference drug 15 mg Mictoryl IR (TID) with regard to the extent of absorption, and maximum and minimum concentrations attained at steady-state. Therefore, both the IR and MR formulations are considered equivalent.

The MR formulation is also equivalent to the reference with regard to the average steady-state serum concentrations reached on the 7^th treatment day (71 vs. 70 ng/mL).

Absorption of propiverine (the medicinal ingredient in Mictoryl/Mictoryl Pediatric) following administration of Mictoryl MR was significantly slower than after Mictoryl IR which resulted in apparently slower elimination (longer half-life) of the MR formulation (absorption-controlled elimination).

Additional randomized controlled studies conducted in the neurogenic detrusor overactivity (NDO) patient population were also included in support of the 45 mg Mictoryl MR dose. However, given the use of Mictoryl in this patient population was not approved by Health Canada (see Indication in Clinical Efficacy); detailed descriptions of these studies were not included as part of the scope of this Summary Basis of Decision (SBD).

For more information, refer to the Mictoryl/Mictoryl Pediatric Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indication

This New Drug Submission for Mictoryl/Mictoryl Pediatric (propiverine hydrochloride) was originally filed with two indications as follows: symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO). However, during the review process, given the limited number of NDO patients evaluated in the submission, together with the absence of a pivotal study with NDO patients, in addition to the noted variability of baseline values and the higher placebo values in the NDO meta-analysis; it was determined that additional, well-designed randomized controlled studies in NDO patients were needed to conduct a thorough evaluation. In view of those deficiencies, and upon request, the sponsor withdrew the NDO indication. Therefore, Health Canada's approved indication is as follows:

Mictoryl/Mictoryl Pediatric (propiverine hydrochloride) is indicated for symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder (OAB).

• Mictoryl 30 mg and 45 mg is indicated in adults including the geriatric population (>65 years of age).
• Mictoryl Pediatric 5 mg is indicated for a body weight adjusted dosing in children from the age of 5 years with OAB up to a body weight of 35 kg. In children and adolescents with a body weight over 35 kg, the maximum recommended dose is 30 mg administered in two daily doses.

Clinical Safety

Safety in the Adult Population

The safety data for 30 mg and 45 mg Mictoryl MR for use in adults for the treatment of OAB was evaluated primarily based on 2,224 patients from the two randomized controlled studies, P 659-1, and P 1300 previously described in the Clinical Efficacy section; in addition to the non-pivotal studies, P 281, P 269, and P 658 conducted in adult patients with OAB and three randomized references studies conducted in NDO patients.

Based on 2,224 patients, the incidence of all treatment-emergent adverse events (TEAEs) ranged from 34.3% to 40.7% for Mictoryl MR, 38.5% to 48.5% for Mictoryl IR, 39.5% for tolterodine ER and 20.3% for placebo. Gastrointestinal disorders accounted for most of the TEAEs reported followed by eye disorders.

The majority of the adverse events (AEs) observed, were those commonly associated with the use of antimuscarinic drugs. These AEs included: dry mouth (IR: 22.8% - 24.2%, MR 17.8% - 29.4%, tolterodine: 26.5% and placebo: 6.4%), constipation (IR 3.8% - 5.0%, MR 3.1% - 6.0%, tolterodine: 1.2% and placebo: 1.0%), eye disorders (IR: 3.8% - 4.5%, MR: 1.0% - 4.6%, placebo: 0.5%), abdominal pain (IR: 1.9% - 2.8%. MR: 0.4% - 1.8%, placebo: 0.0%), and headache (IR: 2.0% - 9.5%, MR: 0.0% - 1.5%, placebo: 0.5%).

Only one serious adverse event (SAE) for 30 mg Mictoryl MR and two for the comparator drug 15 mg Mictoryl IR were observed. All SAE events were judged as unlikely related/unrelated to Mictoryl treatment.

Patient withdrawal was 8.4% in total with 4.3% due to AEs, 0.6% lack of efficacy and 4.0% other causes.

There have been reports of QT interval prolongations with antimuscarinic agents, specifically in the same class of drugs as that of propiverine hydrochloride (medicinal ingredient in Mictoryl/Mictoryl Pediatric). Some drugs that cause QT/QTc interval prolongation may increase the risk of rare, but serious ventricular arrhythmia-torsades de pointes. Patients at risk for QT/QTc interval prolongation, such as those with clinically relevant heart failure, long QT syndrome, recent significant hypokalemia or receiving other drugs known to prolong QT/QTc, should be appropriately monitored when treated with propiverine hydrochloride. Patients who develop prolonged QT/QTc or symptoms of possible arrhythmia such as dizziness, palpitations or fainting should be evaluated electrocardiographically and for electrolyte disturbances.

Propiverine, like other anticholinergics, induces mydriasis. Therefore, the risk to induce acute angle-closure glaucoma in individuals predisposed with narrow angles of the anterior chamber may be increased. Drugs of this class, including propiverine, have been reported to induce or precipitate acute angle-closure glaucoma.

No clinical data are available on the use of Mictoryl in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Therefore Mictoryl should not be used during pregnancy. Also, no clinical data are available on the use of Mictoryl in breast-feeding women. The drug is secreted into the milk of lactating mammals. A risk to the new-borns cannot be excluded. Therefore, Mictoryl should not be administered to breast-feeding women.

Caution should be exercised in patients with mild hepatic impairment when treating them with Mictoryl. Hepatic function should be closely monitored during the treatment period. If liver enzymes and/ or blood bilirubin increase beyond normal values, it is recommended that Mictoryl treatment be discontinued. For patients with moderate or severe hepatic impairment, no studies have been performed to investigate the use of Mictoryl in this patient population. Therefore, use of Mictoryl in these patients is not recommended.

Caution should also be exercised in patients with mild or moderate renal impairment when treating them with Mictoryl. In patients with severe renal impairment (creatinine clearance <30 mL/min), the maximum daily dose of Mictoryl is 30 mg. Therefore, 45 mg Mictoryl MR capsules are not recommended in patients with severe renal failure. Also, pollakiuria and nocturia due to renal diseases should be ruled out prior to initiating treatment with Mictoryl.

Safety in the Pediatric Population

The safety data for 5 mg Mictoryl Pediatric IR for use in children age 5 years or older for the treatment of OAB was evaluated primarily based on study P 1169 previously described in the Clinical Efficacy section. A total of 171 children were included in the safety analysis (87 in the Mictoryl Pediatric group and 84 in the placebo group). Mean age was 7.0 years and mean body mass index was 16.31 kg/m².

Overall, results from the P 1169 study demonstrated that a total of 37 (21.6%) of patients experienced at least one TEAE (20 patients in the Mictoryl Pediatric group and 17 patients in the placebo group). The most commonly reported TEAEs, based on system organ class, were infections and infestations (13.8% Mictoryl Pediatric group vs. 15.5% placebo group); gastrointestinal disorders (9.2% Mictoryl Pediatric group vs. 3.6% placebo group); eye disorders (2.3% Mictoryl Pediatric group only); nervous system disorders (2.3% Mictoryl Pediatric group vs. 1.2% placebo group). In addition, three patients in the Mictoryl Pediatric group experienced prolongations of QTc interval (Bazett and Fridericia) by at least 60 msec, upon re-assessment, only the Bazett prolongations were confirmed and not the Fridericia.

Given the complex process of the bladder and its development, it is recommended that use of Mictoryl Pediatric not start earlier than at the age of 5 years in children with OAB. Also, treatment of children and adolescents should be administered within the framework of an overall therapeutic approach ("urotherapy" in cases of OAB).

There exists very limited data on liver function tests in the pediatric population while receiving Mictoryl Pediatric therapy. In addition, there is also limited safety data available for long-term use of Mictoryl Pediatric (1 year and beyond).

A few uncertainties remain in regard to the use of Mictoryl Pediatric for the treatment of OAB in the pediatric population. First, there was no dedicated cardiac safety study conducted specifically for the pediatric indication apart from the electrocardiogram (ECG) data (including QTc prolongation) collected in the P 1169 study. Furthermore, no pediatric drug interaction studies were conducted. There also exists very limited data on liver function tests in the pediatric population. There is also limited safety data available for long-term use of Mictoryl Pediatric (1 year and beyond). For the purpose of authorization of this medicinal product in pediatric indication, these uncertainties have been adequately labelled in the Mictoryl/Mictoryl Pediatric Product Monograph and with the Risk Management Plan (RMP) management strategies.

For more information, refer to the Mictoryl/Mictoryl Pediatric Product Monograph, approved by Health Canada and available through the Drug Product Database.