Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands
Pharmacotherapeutic group: Urologicals, Drugs for urinary frequency and incontinence
ATC code: G04BD08
Solifenacin is a competitive, specific cholinergic-receptor antagonist.
The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of which the M3 subtype is predominantly involved. In vitro and in vivo pharmacological studies indicate that solifenacin is a competitive inhibitor of the muscarinic M3 subtype receptor. In addition, solifenacin showed to be a specific antagonist for muscarinic receptors by displaying low or no affinity for various other receptors and ion channels tested.
Treatment with Vesicare in doses of 5 mg and 10 mg daily was studied in several double blind, randomised, controlled clinical trials in men and women with overactive bladder.
As shown in the table below, both the 5 mg and 10 mg doses of Vesicare produced statistically significant improvements in the primary and secondary endpoints compared with placebo. Efficacy was observed within one week of starting treatment and stabilises over a period of 12 weeks. A long-term open label study demonstrated that efficacy was maintained for at least 12 months. After 12 weeks of treatment approximately 50% of patients suffering from incontinence before treatment were free of incontinence episodes, and in addition 35% of patients achieved a micturition frequency of less than 8 micturitions per day. Treatment of the symptoms of overactive bladder also results in a benefit on a number of Quality of Life measures, such as general health perception, incontinence impact, role limitations, physical limitations, social limitations, emotions, symptom severity, severity measures and sleep/energy.
Results (pooled data) of four controlled Phase 3 studies with a treatment duration of 12 weeks:
| Placebo | Vesicare 5 mg o.d. | Vesicare 10 mg o.d. | Tolterodine 2 mg b.i.d. | |
|---|---|---|---|---|
| No. of micturitions/24 h | ||||
| Mean baseline | 11.9 | 12.1 | 11.9 | 12.1 |
| Mean reduction from baseline | 1.4 | 2.3 | 2.7 | 1.9 |
| % change from baseline | (12%) | (19%) | (23%) | (16%) |
| n | 1138 | 552 | 1158 | 250 |
| p-value* | <0.001 | <0.001 | 0.004 | |
| No. of urgency episodes/24 h | ||||
| Mean baseline | 6.3 | 5.9 | 6.2 | 5.4 |
| Mean reduction from baseline | 2.0 | 2.9 | 3.4 | 2.1 |
| % change from baseline | (32%) | (49%) | (39%) | |
| n | 1124 | 548 | 1151 | 250 |
| p-value* | <0.001 | <0.001 | 0.031 | |
| No. of incontinence episodes/24 h | ||||
| Mean baseline | 2.9 | 2.6 | 2.9 | 2.3 |
| Mean reduction from baseline | 1.1 | 1.5 | 1.8 | 1.1 |
| % change from baseline | (38%) | (58%) | (48%) | |
| n | 781 | 314 | 778 | 157 |
| p-value* | <0.001 | <0.001 | 0.009 | |
| No. of nocturia episodes/24 h | ||||
| Mean baseline | 1.8 | 2.0 | 1.8 | 1.9 |
| Mean reduction from baseline | 0.4 | 0.6 | 0.6 | 0.5 |
| % change from baseline | (22%) | (30%) | (33%) | (26%) |
| n | 1005 | 494 | 1035 | 232 |
| p-value* | 0.025 | <0.001 | 0.199 | |
| Volume voided/micturition | ||||
| Mean baseline | 166 ml | 146 ml | 163 ml | 147 ml |
| Mean increase from baseline | 9 ml | 32 ml | 43 ml | 24 ml |
| % change from baseline | (5%) | (21%) | (26%) | (16%) |
| n | 1135 | 552 | 1156 | 250 |
| p-value* | <0.001 | <0.001 | <0.001 | |
| No. of pads/24 h | ||||
| Mean baseline | 3.0 | 2.8 | 2.7 | 2.7 |
| Mean reduction from baseline | 0.8 | 1.3 | 1.3 | 1.0 |
| % change from baseline | (27%) | (46%) | (48%) | (37%) |
| n | 238 | 236 | 242 | 250 |
| p-value* | <0.001 | <0.001 | 0.010 | |
Note: In 4 of the pivotal studies, Vesicare 10 mg and placebo were used. In 2 out of the 4 studies also Vesicare 5 mg was used and one of the studies included tolterodine 2 mg bid.
Not all parameters and treatment groups were evaluated in each individual study. Therefore, the numbers of patients listed may deviate per parameter and treatment group.
* P-value for the pair wise comparison to placebo
Children and adolescents (age 5 years and older):
Treatment with Vesicare oral suspension was studied in two clinical studies. A 12-week double-blind, randomised, placebo-controlled, clinical trial (905-CL-076) was performed in 189 paediatric patients with OAB (73 children aged 5 to 11 years and 22 adolescents aged 12 to 17 years were treated with solifenacin). This was followed by a 40-week long-term open-label extension study (905-CL-077) in 148 paediatric patients (119 children and 29 adolescents were treated with solifenacin). In both studies, the majority of patients were up-titrated to the weight-based equivalent of 10 mg in adults.
In study 905-CL-076 Vesicare oral suspension did not show a statistically significant improvement in the primary endpoint of mean volume voided per micturition compared with placebo in the overall population.
In children (aged 5 to 11 years) a statistically significant difference was observed for this primary endpoint. No statistically significant improvement was observed in the secondary endpoints of micturition frequency, number of incontinence episodes per day and number of dry days per week. No unexpected or unlisted adverse events were reported for the entire dose range tested.
In the open-label extension study, no unexpected or unlisted adverse events were reported. The safety profile for solifenacin in paediatric patients during long-term exposure was comparable to that observed in adults.
Children and adolescents (age 6 months to less than 18 years):
Vesicare oral suspension was evaluated in two 52-week, open-label, baseline-controlled, sequential dose titration studies for the treatment of neurogenic detrusor overactivity (NDO) in paediatric patients aged 6 months to less than 18 years (studies 905-CL-074 and 905-CL-047).
In study 905-CL-074, a total of 4 subjects aged 6 months to less than 2 years and 19 subjects aged 2 to less than 5 years of age received treatment with Vesicare oral suspension, while in study 905-CL-047, a total of 76 subjects aged 5 to less than 18 years of age received treatment with Vesicare oral suspension.
In both studies the primary endpoint was the change from baseline in maximum cystometric capacity (MCC) after 24 weeks of Vesicare oral suspension treatment. Children treated with Vesicare oral suspension had a statistically significant increase in MCC compared with baseline after 24 weeks of treatment.The magnitude of the observed changes in both the primary and secondary endpoints in children (5 to less than 12 years of age) and in adolescents (12 to less than 18 years of age) was comparable.
The results for the primary endpoint in the clinical studies of Vesicare oral suspension in pediatric patients with NDO are reported in the table below. Treatment effects were maintained over 52-weeks.
Change from Baseline to 24 Weeks for Vesicare oral suspension:
| Parameter | Aged 6 months to Less than 5 Years | Aged 5 to Less than 18 Years |
|---|---|---|
| Mean (SD, n) | Mean (SD, n) | |
| Primary Endpoint | ||
| Maximum Cystometric Capacity (ml) | ||
| Baseline | 92.3 (38.2, 21) | 223.7 (132.9, 55) |
| Week 24 | 129.4 (40.2, 21) | 279.1 (126.8, 49) |
| Change from baseline | 37.0 (35.9, 21) | 57.2 (107.7, 49) |
| P = <0.001 | P = <0.001 | |
| 95% CI: 20.7, 53.4 | 95% CI: 26.3, 88.1 | |
Secondary urodynamic measurements also demonstrated an improvement from baseline to 24 weeks in both age groups. In subjects aged 6 months to less than 5 years of age, bladder compliance increased (mean change: 5.1 ml/cmH2O; SD: 6.82; 95% CI: 2.0, 8.2), number of overactive contractions >15 cmH2O decreased (mean change: -7.0; SD: 8.6; 95% CI: -11.0, -3.1) and bladder volume until first detrusor contraction >15 cmH2O, expressed as % of expected bladder capacity, improved (baseline median: 38.00%; week 24 median 99.89%). In subjects aged 5 to less than 18 years of age, bladder compliance increased (mean change: 9.1 ml/cmH2O; SD: 28.6; 95% CI: 1.0, 17.2), number of overactive contractions >15 cmH2O decreased (mean change: -2.3; SD: 5.1; 95% CI: -3.7, -0.8) and bladder volume until first detrusor contraction >15 cmH2O, expressed as % of expected bladder capacity, improved (baseline median: 28.25%; week 24 median 58.28%).
Additional diary-based measurements demonstrated improvement from baseline to 24 weeks in both age groups. In subjects aged 6 months to less than 5 years of age, the average maximum catheterized volume per day increased (mean change: 40.3 ml; SD: 50.0; 95% CI: 16.2, 64.4), and average number of periods between clean intermittent catheterisations with incontinence episodes per 24 hours decreased (mean change: -1.31; SD: 1.35; 95% CI: -1.99, -0.64). In subjects aged 5 to less than 18 years, the average maximum catheterized volume per day increased (mean change: 67.45 ml; SD: 88.07; 95% CI: 42.68, 92.22) and the average number of incontinence episodes per 24 hours decreased (mean change: -1.60; SD: 2.04; 95% CI: -2.18, -1.03).
The treatment with Vesicare oral suspension in children and adolescents was well-tolerated at all dose levels. No new safety concerns were identified compared with the known safety profile of solifenacin in adults.
There is no clinical study data available beyond one year in treatment of NDO in children and adolescents.
There is insufficient clinical experience in paediatric patients with NDO less than 2 years of age. Clinical studies have not been conducted in paediatric patients with NDO less than 6 months of age.
After oral intake of solifenacin by adults, maximum solifenacin plasma concentrations (Cmax) are reached after 4 to 12 hours. The tmax is independent of the dose. The Cmax and area under the curve (AUC) increase in proportion to the dose between 5 to 40 mg. Absolute bioavailability is approximately 90%.
Food intake does not affect the Cmax and AUC of solifenacin.
The apparent volume of distribution of solifenacin following intravenous administration is about 600 L. Solifenacin is to a great extent (approximately 98%) bound to plasma proteins, primarily α1-acid glycoprotein.
Solifenacin is extensively metabolised by the liver, primarily by cytochrome P450 3A4 (CYP3A4). However, alternative metabolic pathways exist, that can contribute to the metabolism of solifenacin. The systemic clearance of solifenacin is about 9.5 L/h and the terminal half-life of solifenacin is 45-68 hours. After oral dosing, one pharmacologically active (4R-hydroxy solifenacin) and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been identified in plasma in addition to solifenacin.
After a single administration of 10 mg [14C-labelled]-solifenacin, about 70% of the radioactivity was detected in urine and 23% in faeces over 26 days. In urine, approximately 11% of the radioactivity is recovered as unchanged active substance; about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite and 8% as the 4R-hydroxy metabolite (active metabolite).
Pharmacokinetics are linear in the therapeutic dose range.
No dosage adjustment based on patient age is required. Studies in elderly have shown that the exposure to solifenacin, expressed as the AUC, after administration of solifenacin succinate (5 mg and 10 mg once daily) was similar in healthy elderly subjects (aged 65 through 80 years) and healthy young subjects (aged less than 55 years). The mean rate of absorption expressed as tmax was slightly slower in the elderly and the terminal half-life was approximately 20% longer in elderly subjects. These modest differences were considered not clinically significant.
The pharmacokinetics of solifenacin following weight-adjusted dosing in children and adolescents with OAB (aged 5 years and older) and NDO (aged 2 to 18 years) were similar to those observed in adults after body weight adjustment, with a slightly shorter tmax and t1/2; these differences were not considered clinically significant.
The pharmacokinetics of solifenacin are not influenced by gender.
The pharmacokinetics of solifenacin are not influenced by race.
The AUC and Cmax of solifenacin in mild and moderate renally impaired patients, was not significantly different from that found in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤30 ml/min) exposure to solifenacin was significantly greater than in the controls with increases in Cmax of about 30%, AUC of more than 100% and t½ of more than 60%. A statistically significant relationship was observed between creatinine clearance and solifenacin clearance.
Pharmacokinetics in patients undergoing haemodialysis have not been studied.
In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the Cmax is not affected, AUC increased with 60% and t½ doubled. Pharmacokinetics of solifenacin in patients with severe hepatic impairment have not been studied.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, fertility, embryofetal development, genotoxicity, and carcinogenic potential. In the pre- and postnatal development study in mice, solifenacin treatment of the mother during lactation caused dose-dependent lower postpartum survival rate, decreased pup weight and slower physical development at clinically relevant levels. Dose related increased mortality without preceding clinical signs occurred in juvenile mice treated from day 10 or 21 after birth with doses that achieved a pharmacological effect and both groups had higher mortality compared to adult mice. In juvenile mice treated from postnatal day 10, plasma exposure was higher than in adult mice; from postnatal day 21 onwards, the systemic exposure was comparable to adult mice. The clinical implications of the increased mortality in juvenile mice are not known. Vesicare oral suspension showed no potential for irritation to the eyes when tested in rabbits.
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