Solifenacin Succinate

The recommended dose of solifenacin succinate tablets is 5 mg once daily. If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily. Solifenacin succinate tablets should be taken with water and swallowed whole. Solifenacin succinate tablets can be administered with or without food.

For patients with severe renal impairment (CL_cr <30 mL/min), a daily dose of solifenacin succinate tablets greater than 5 mg is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6) ].

For patients with moderate hepatic impairment (Child-Pugh B), a daily dose of solifenacin succinate tablets greater than 5 mg is not recommended. Use of solifenacin succinate tablets in patients with severe hepatic impairment (Child-Pugh C) is not recommended [see Warnings and Precautions (5.6) and Use in Specific Populations (8.7) ].

When administered with potent CYP3A4 inhibitors such as ketoconazole, a daily dose of solifenacin succinate tablets greater than 5 mg is not recommended [see Drug Interactions (7.1) ].

Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, solifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. Anaphylactic reactions have been reported rarely in patients treated with solifenacin succinate. Solifenacin succinate should not be used in patients with a known or suspected hypersensitivity to solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.

Solifenacin succinate, like other anticholinergic drugs, should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4) ].

Solifenacin succinate, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility [see Contraindications (4) ].

Solifenacin succinate is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2) ]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how solifenacin succinate affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Solifenacin succinate should be used with caution in patients being treated for narrow-angle glaucoma [see Contraindications (4) ].

Solifenacin succinate should be used with caution in patients with hepatic impairment. Doses of solifenacin succinate greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin succinate is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3) and Use in Specific Populations (8.7) ].

Solifenacin succinate should be used with caution in patients with renal impairment. Doses of solifenacin succinate greater than 5 mg are not recommended in patients with severe renal impairment (CL_cr<30 mL/min) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6) ].

In a study of the effect of solifenacin on the QT interval in 76 healthy women [see Clinical Pharmacology (12.2) ] the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe solifenacin succinate for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Solifenacin has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. Expected adverse reactions of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The incidence of dry mouth and constipation in patients treated with solifenacin was higher in the 10 mg compared to the 5 mg dose group.

In the four 12-week double-blind clinical trials, severe fecal impaction, colonic obstruction, and intestinal obstruction were reported in one patient each, all in the solifenacin 10 mg group. Angioneurotic edema has been reported in one patient taking solifenacin 5 mg. Compared to 12 weeks of treatment with solifenacin, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months. 

The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events, in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Solifenacin 5 or 10 mg once daily for up to 12 weeks.

Table 1: Percentages of Patients with Identified Adverse Reactions, Derived from All Adverse Events Exceeding Placebo Rate and Reported by 1% or More Patients for Combined Pivotal Studies

Because these spontaneously reported events are from the worldwide postmarketing experience, the frequency of events and the role of solifenacin in their causation cannot be reliably determined.

The following events have been reported in association with solifenacin use in worldwide postmarketing experience:

General: peripheral edema, hypersensitivity reactions, including angioedema with airway obstruction, rash, pruritus, urticaria, and anaphylactic reaction;

Central Nervous: headache, confusion, hallucinations, delirium, and somnolence;

Cardiovascular: QT prolongation,Torsade de Pointes, atrial fibrillation, tachycardia, and palpitations;

Hepatic: liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), and GGT (gamma-glutamyl transferase);

Renal: renal impairment;

Metabolism and nutrition disorders: decreased appetite and hyperkalemia;
Dermatologic: exfoliative dermatitis, erythema multiforme, and dry skin;

Eye disorders: glaucoma;

Gastrointestinal disorders: gastroesophageal reflux disease, ileus, abdominal pain, and dysgeusia;
Respiratory, thoracic and mediastinal disorders: dysphonia and nasal dryness;
Musculoskeletal and connective tissue disorders: muscular weakness.

Following the administration of 10 mg of solifenacin in the presence of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, the mean Cmax and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively. Therefore, it is recommended not to exceed a 5 mg daily dose of solifenacin when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. The effects of weak or moderate CYP3A4 inhibitors were not examined.

There were no in vivo studies conducted to evaluate the effect of CYP3A4 inducers on solifenacin. In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Therefore, inducers of CYP3A4 may decrease the concentration of solifenacin.

At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.

Solifenacin has no significant effect on the pharmacokinetics of R-warfarin or S-warfarin [see Clinical Pharmacology (12.3) ].

In the presence of solifenacin there are no significant changes in the plasma concentrations of combined oral contraceptives (ethinyl estradiol/levonorgestrel) [see Clinical Pharmacology (12.3) ].

Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects [see Clinical Pharmacology (12.3) ].

Pregnancy Category C  

There are no adequate and well-controlled studies in pregnant women.

Reproduction studies have been performed in mice, rats and rabbits. After oral administration of ¹⁴C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The effect of solifenacin on labor and delivery in humans has not been studied.

There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality.

After oral administration of ¹⁴C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD]. Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period.

It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, solifenacin should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue solifenacin in nursing mothers.

The safety and effectiveness of solifenacin in pediatric patients have not been established.

In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients < 65 years) treated with solifenacin. 

Multiple dose studies of solifenacin in elderly volunteers (65 to 80 years) showed that Cmax, AUC and t1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years).

Solifenacin 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 t1/2 of solifenacin in patients with severe renal impairment. Doses of solifenacin greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min) [see Warnings and Precautions (5.7)  and Dosage and Administration (2.2)].

Solifenacin should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.6) and Dosage and Administration (2.3) ].

The pharmacokinetics of solifenacin is not significantly influenced by gender.

Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.

Cardiac Electrophysiology  

The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Subjects were 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. Study subjects were female volunteers aged 19 to 79 years. 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 those observed upon co-administration of 10 mg solifenacin with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG 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. Representative results are shown in Table 2.

Table 2: QTc changes in msec (90%CI) from baseline at Tmax (relative to placebo)*

*Results displayed are those derived from the parallel design portion of the study and represent the comparison of Group 1 to time-matched placebo effects in Group 2

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% CI) in QTcF for moxifloxacin in the three sessions were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively.

The QT interval prolonging effect appeared 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.

Absorption  

After oral administration of solifenacin to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.

Effect of Food  

Solifenacif may be administered without regard to meals. A single 10 mg dose administration of solifenacin with food increased Cmax and AUC by 4% and 3%, respectively.

Distribution  

Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to ^∝1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L.

Metabolism  

Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways 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-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.

Excretion

Following the administration of 10 mg of ¹⁴C-solifenacin succinate to healthy volunteers, 69.2% of the radioactivity was recovered in the urine and 22.5% in the feces over 26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy solifenacin and 4R-hydroxy-N-oxide of solifenacin and in feces 4R-hydroxy solifenacin. The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours.

Drug Interactions  

Potent CYP3A4 Inhibitors  

In a crossover study, following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor, ketoconazole 400 mg, once daily for 21 days, the mean Cmax and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively [see Dosage and Administration (2.4) and Drug Interactions (7.1) ].

Warfarin  

In a crossover study, subjects received a single oral dose of warfarin 25 mg on the 10^th day of dosing with either solifenacin 10 mg or matching placebo once daily for 16 days. For R-warfarin when it was coadministered with solifenacin, the mean Cmax increased by 3% and AUC decreased by 2%. For S-warfarin when it was coadministered with solifenacin, the mean Cmax and AUC increased by 5% and 1%, respectively [see Drug Interactions (7.4) ].

Oral Contraceptives  

In a crossover study, subjects received 2 cycles of 21 days of oral contraceptives containing 30 ug ethinyl estradiol and 150 ug levonorgestrel. During the second cycle, subjects received additional solifenacin 10 mg or matching placebo once daily for 10 days starting from 12^th day of receipt of oral contraceptives. For ethinyl estradiol when it was administered with solifenacin, the mean Cmax and AUC increased by 2% and 3%, respectively. For levonorgestrel when it was administered with solifenacin, the mean Cmax and AUC decreased by 1% [see Drug Interactions (7.5) ].

Digoxin  

In a crossover study, subjects received digoxin (loading dose of 0.25 mg on day 1, followed by 0.125 mg from days 2 to 8) for 8 days. Consecutively, they received solifenacin 10 mg or matching placebo with digoxin 0.125 mg for additional 10 days. When digoxin was coadministered with solifenacin, the mean Cmax and AUC increased by 13% and 4%, respectively [see Drug Interactions (7.6) ].

No increase in tumors was found following the administration of solifenacin succinate to male and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times, respectively, of the exposure at the maximum recommended human dose [MRHD] of 10 mg), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times the exposure at the MRHD).

Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood lymphocytes with or without metabolic activation, or in the in vivo micronucleus test in rats.

Solifenacin succinate had no effect on reproductive function, fertility or early embryonic development of the fetus in male and female mice treated with 250 mg/kg/day (13 times the exposure at the MRHD) of solifenacin succinate, and in male rats treated with 50 mg/kg/day (<1 times the exposure at the MRHD) and female rats treated with 100 mg/kg/day (1.7 times the exposure at the MRHD) of solifenacin succinate.