Urinary antispasmodics. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergic mediated functions, including contractions of urinary bladder smooth muscle and stimulation of the salivary secretion.
Four randomised, double blind, placebo controlled pivotal studies were performed of 12 weeks duration to assess solifenacin for the treatment of overactive bladder in patients having symptoms of urinary frequency, urgency and/or urge or mixed incontinence (with the predominance of urge). Entry criteria required that patients have symptoms of overactive bladder for ≥3 months duration. These studies involved 3027 patients (1811 on solifenacin and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg solifenacin doses and the other two evaluated only the 10 mg dose. The studies assessed the standard primary efficacy endpoint of number of micturitions per 24 hours, along with a number of usual secondary endpoints, including incontinence episodes, urgency episodes, urge incontinence episodes, nocturia episodes, all per 24 hours, and volume voided per micturition, using patient diaries.
As shown in the table as follows, 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. 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. All patients completing the 12-week studies were eligible to enter an open label, long term extension study and 81% of patients enrolling completed the additional 40-week treatment period demonstrating a maintenance of effect. 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. (See Table 1.)
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Clinical QT Interval Data:
Two dedicated QT studies have been performed with solifenacin.
The first study was an open label, multiple dose escalating study in 60 healthy subjects. In this study solifenacin was administered starting at a dose of 10 mg once daily for 2 weeks and proceeded in 10 mg increments for 2 weeks at each dose level. The highest tolerated dose was 40 mg. The results are presented in the table as follows. There was no significant change in QTc interval using the Bazett as well as the Friderica method for the 10 mg solifenacin compared to baseline. Depending on the method applied, some prolongation was seen for the 20 mg and 30 mg doses, which are higher than the recommended therapeutic dose. However, both methods suggest no prolongation for the 40 mg dose, which is four times the highest recommended therapeutic dose. (See Table 2.)
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There were no QTc intervals >500 msec; increases of >60 msec occurred in 1 subject (on 30 mg), while change <60 msec but >30 msec occurred in 34 subjects (11 changes on 10 mg, 20 changes on 20 mg, 27 changes on 30 mg, 9 changes on 40 mg).
The second study was a double blind, multiple dose, placebo and positive controlled (moxifloxacin 400 mg) study in 76 female volunteers aged 19 to 79 years. This second QT study was a dedicated thorough QT study with the subjects randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg, while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers the exposure observed upon co-administration of 10 mg Vesicare with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline ECG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.
The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis (Fridericia method). Representative results for solifenacin are shown in the table as follows. (See Table 3.)
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Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions. The placebo subtracted mean changes (90% Confidence Interval) in QTcF for moxifloxacin in the three sessions were 11 msec (7, 14), 12 msec (8, 17) and 16 msec (12, 21), respectively.
There were no subjects with a mean QTc >500 msec. Four subjects experienced increases in mean QTcF that were greater than 60 msec from the time-matched baseline. Three subjects received 30 mg solifenacin and the fourth received 400 mg moxifloxacin.
A change in QTc of <60 msec but >30 msec occurred in 29 subjects on 10 mg and in 31 subjects during 30 mg solifenacin treatment.
The QT interval prolonging effect appeared to be greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.
Across the four controlled phase 3 studies, QTc interval prolongation was seen of approximately up to 5 msec, along with PR interval prolongation. There were 12 patients with a change in QTc from baseline of >60 msec and 6 patients with QTc >500 msec at any time point on solifenacin. There were no reports of VT or VF or association between these QT changes and death, syncope, dizziness or ventricular arrhythmias.
After intake of Vesicare tablets, maximum solifenacin plasma concentrations (Cmax
) are reached after 3 to 8 hours and at steady state ranged from 32.3 to 69.9 ng/ml for the 5 and 10 mg Vesicare tablets, respectively. 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
: Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathway exist. The primary metabolic routes of solifenacin are through N
-oxidation of the quinuclidin ring and 4R
-hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R
-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N
-glucuronide and the N
-oxide and 4R
-oxide of solifenacin) have been found in human plasma after oral dosing.
: After a single administration of 10 mg [14
C-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
-oxide metabolite and 8% as the 4R
-hydroxy metabolite (active metabolite). The systemic clearance of solifenacin is about 9.5 L/h. The elimination half-life of solifenacin following chronic dosing is approximately 45 - 68 hours.
Pharmacokinetics are linear in the therapeutic dose range.
: Vesicare should be used with caution in patients with renal impairment. There is a 2.1-fold increase in AUC and 1.6-fold increase in t½
of solifenacin in patients with severe renal impairment. Doses of Vesicare greater than 5 mg are not recommended in patients with severe renal impairment (CLcr
<30 ml/min) (see Precautions and Dosage & Administration).
Vesicare should be used with caution in patients with hepatic impairment. There is a 2-fold increase in the t½
and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of Vesicare greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B).
Vesicare is not recommended for patients with severe hepatic impairment (Child-Pugh C) (see Precautions and Dosage & Administration).
The pharmacokinetics of solifenacin have not been established in children and adolescents.