Vesicare

Interactions with herbal products have not been established and caution should be taken if such agents are used by patients.

In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Inducers or inhibitors of CYP3A4 may alter solifenacin pharmacokinetics. Therefore, the dose of solifenacin should be maintained at, or dropped to, 5 mg daily while patients are taking a potent CYP3A4 inhibitor such as ketoconazole, clarithromycin, erythromycin, diclofenac, nefazodone, verapamil and others.

Co-ingestion of grapefruit juice with VESICARE may increase the serum level of solifenacin.

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

Interactions with laboratory tests have not been investigated.

Concomitant medication with other medicinal products with anticholinergic properties may result in more pronounced therapeutic effects and undesirable effects. An interval of approximately 1 week should be allowed after stopping treatment with VESICARE, before commencing other anticholinergic therapy.

The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists. Solifenacin may reduce the effect of medicinal products that stimulate the motility of the gastrointestinal tract, such as metoclopramide.

For patients with moderate hepatic impairment (Child-Pugh B), a daily dose of VESICARE greater than 5 mg is not recommended. Use of VESICARE in patients with severe hepatic impairment (Child Pugh C) is not recommended.

For patients with severe renal impairment (CL_cr <30 mL/min), a daily dose of VESICARE greater than 5 mg is not recommended. VESICARE is contraindicated in dialysis dependent patients (see Contraindications).

The recommended dose of VESICARE is 5 mg once daily. If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily.

VESICARE should be taken with liquids and swallowed whole. VESICARE can be administered with or without food, without regard to meals.

The maximum effect can be determined after 4 weeks at the earliest.

If a dose is missed, the next tablet should be taken as planned. Doses should not be doubled to make up for a missed dose.

When administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors, a daily dose of VESICARE should be maintained at, or dropped to, 5 mg daily.

One young male subject developed a reversible increase in hepatic enzymes following a single dose of solifenacin during a Phase I study. Although causality has not been established, special attention should be paid to subjects who develop abnormal liver function tests after starting solifenacin and consideration given to discontinuing treatment.

Expected side effects of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The most common adverse events reported in patients treated with VESICARE were dry mouth and constipation and the incidence of these side effects was higher in the 10 mg compared to the 5 mg dose group. Compared to twelve weeks of treatment with VESICARE, the incidence and severity of adverse events were similar in patients who remained on drug for up to 12 months. The most frequent reason for discontinuation due to an adverse event was dry mouth, 1.5%.

In addition to the adverse events observed in clinical trials, the following events have been reported in association with VESICARE (solifenacin succinate) use in worldwide post-marketing experience, although the frequency of events or a causal relationship with VESICARE could not always be confirmed: urinary retention; vomiting; peripheral edema; hypersensitivity reactions including rash, pruritus, and urticaria; dizziness; headache; and hallucination.

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 VESICARE (see Action and Clinical Pharmacology).

Safety and effectiveness in children have not yet been established.

Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg daily (5 times the maximum recommended therapeutic dose) and resolved within 7 days following discontinuation of drug.

Overdosage with VESICARE can potentially result in severe anticholinergic effects and should be treated accordingly. The highest dose of solifenacin succinate accidentally given to a single patient was 280 mg in a 5-hour period, resulting in mental status changes. The patient was given charcoal treatment and recovered without sequelae.

In the event of overdose with VESICARE treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.

Each light pink, round, film-coated tablet, debossed with logo 151, contains: solifenacin succinate 10 mg (equivalent to solifenacin 7.5 mg). Nonmedicinal ingredients: corn starch, hypromellose 2910, lactose monohydrate, magnesium stearate, polyethylene glycol 8000, red ferric oxide, talc and titanium dioxide. Bottles and unit dose blister packages.

Each light yellow, round, film-coated tablet, debossed with logo 150, contains: solifenacin succinate 5 mg (equivalent to solifenacin 3.8 mg). Nonmedicinal ingredients: corn starch, hypromellose 2910, lactose monohydrate, magnesium stearate, polyethylene glycol 8000, talc, titanium dioxide and yellow ferric oxide. Bottles and unit dose blister packages.

Use with caution in patients with reduced renal function. Doses of VESICARE greater than 5 mg are not recommended in patients with severe renal impairment (CL_cr <30 mL/min) (see Action and Clinical Pharmacology, Dosage and Administration). VESICARE is contraindicated in dialysis dependent patients (see Contraindications).

VESICARE, like other anticholinergics should be used with caution in patients with decreased gastrointestinal motility.

Solifenacin succinate was not mutagenic in the in vitro S. typhimurium or E. 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.

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 human exposure at the maximum recommended human dose [MRHD], respectively), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times exposure at the MRHD).

VESICARE, like other anticholinergic drugs, should be administered with caution in patients with impaired ability to sweat, to reduce the risk of heat prostration, and in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

VESICARE may cause blurred vision. Patients should be advised to exercise caution in driving or operating machinery until the drug's effect on vision has been determined.

Monitoring of the QT/QTc interval and/or serum electrolyte levels may be appropriate in high risk patients who are being treated with VESICARE, such as: patients with known congenital or acquired QT/QTc interval prolongation or electrolyte disturbances; patients who are taking drugs that have been associated with QT/QTc interval prolongation and/or torsades de pointes such as Class IA (eg quinidine, procainamide) or Class III (eg amiodarone, sotalol) antiarrhythmic medications or those taking potent CYP3A4 inhibitors.

There are no adequate and well-controlled studies investigating the effects of solifenacin succinate in pregnant women. Animal reproduction studies are not always predictive of human response; therefore, VESICARE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women of childbearing potential should be considered for treatment only if using adequate contraception.

Reproduction studies have been performed in mice, rats and rabbits. After oral administration of ¹⁴C-solifenacin succinate to pregnant mice, drug-related material has been shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 30 mg/kg/day (1.2 times exposure at the maximum recommended human dose [MRHD]). Administration of solifenacin succinate to pregnant mice, at doses of 100 mg/kg and greater (3.6 times exposure at the MRHD), during the major period of organ development resulted in reduced fetal body weights. Administration of 250 mg/kg/kg (7.9 times exposure at 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 100 mg/kg/day and greater (3.6 times exposure at 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 exposure at the MRHD) or in rabbits at up to 50 mg/kg/day (1.8 times exposure at the MRHD).

The effect of VESICARE on labor and delivery in humans has not been studied. There were no effects on natural delivery in mice treated with 30 mg/kg/day (1.2 times exposure at the MRHD). Administration of solifenacin succinate at 100 mg/kg/day (3.6 times exposure at the MRHD) or greater increased peripartum pup mortality.

No clinical data are available from reproductively competent women who have received long-term treatment with VESICARE. The potential risk to such women is presently unknown. Therefore, VESICARE should be used during pregnancy only if the potential benefit for the mother justifies the potential risk for the fetus. Women of childbearing potential should be considered for treatment only if using adequate contraception.

In a 13-week toxicity study in mice treated with 400 mg/kg/day [15 times exposure at the maximum recommended human dose (MRHD)] of solifenacin succinate and in a 26-week toxicity study in rats treated with 30 mg/kg/day (<1 times exposure at the MRHD) or greater of solifenacin succinate, follicular degeneration/reduced corpora lutea in the ovaries and/or uterine atrophy were observed in female animals that died or were sacrificed in extremis. Low uterine weight and uterine immaturity were observed in female dogs treated with 3 mg/kg/day (<1 times exposure at the MRHD) or greater of solifenacin succinate in the 13-week toxicity study.

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 exposure at the MRHD) of solifenacin succinate for 4 weeks and 2 weeks, respectively, and in male rats treated with 50 mg/kg/day (<1 times exposure at the MRHD) for 4 weeks and female rats treated with 100 mg/kg/day (1.7 times exposure at the MRHD) for 2 weeks.

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

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 30 mg/kg/day (1.2 times exposure at the maximum recommended human dose [MRHD]). Pups of female mice treated with 100 mg/kg/day (3.6 times 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.

A study of the effect of solifenacin on the QT interval was conducted in 76 healthy women. The QTc interval prolongation 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 interval overlapped. This study was not designed to draw direct statistical comparison between the drugs or the dose levels (see Action and Clinical Pharmacology). This observation should be considered in clinical decisions to prescribe VESICARE for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

The effect of solifenacin on QTc interval change in males has not been investigated, and caution should be taken in extrapolating the findings of this study to male subjects.

The effect of solifenacin on QTc interval change in elderly subjects with occult renal insufficiency, (in whom plasma concentration of solifenacin might be higher than those observed in younger subjects), has not been investigated.

VESICARE should be used with caution in patients with reduced hepatic function. 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 Action and Clinical Pharmacology, Dosage and Administration and Adverse Reactions).

VESICARE should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t_1/2 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 Warnings and Precautions, Dosage and Administration).

Multiple dose studies of VESICARE in elderly volunteers (65 to 80 years) showed that C_max, AUC and t_1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years) (see Indications and Clinical Use).

Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to α₁-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L.

After oral administration of VESICARE to healthy volunteers, peak plasma levels (C_max) 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 VESICARE tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.

Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Solifenacin is a competitive muscarinic receptor antagonist with selectivity for the urinary bladder over salivary glands in vitro and in vivo (mice, rats and monkeys). In cells isolated from rats and monkeys, solifenacin inhibited carbachol-induced intracellar calcium mobilization more potently in bladder smooth muscle cells than in salivary gland cells. The bladder selectivity of solifenacin in monkeys is significantly greater than those of other antimuscarinics as illustrated by selectivity ratios (bladder/salivary gland) of 2.1, 0.51, 0.65, 0.46 and 0.61 for solifenacin, oxybutynin, tolterodine, darifenacin and atropine, respectively. In anesthetized rats, solifenacin is also more potent in inhibiting carbachol-induced increases in intravesical pressure than in inhibiting salivary secretion. Although other antimuscarinics also showed some tissue selectivity, the selectivity ratio of solifenacin (6.5) estimated from its potency to inhibit urinary bladder and salivary gland was the greatest among all antimuscarinics tested (1.0 to 2.4).

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.

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 t_1/2 of solifenacin in patients with severe renal impairment. Doses of VESICARE greater than 5 mg are not recommended in patients with severe renal impairment (CL_cr <30 mL/min) (see Warnings and Precautions, Dosage and Administration). VESICARE is contraindicated in dialysis dependent patients (see Contraindications).

The pharmacokinetics of solifenacin are not significantly influenced by gender.

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.

There is no significant effect of food on the pharmacokinetics of solifenacin.

The effect of moxifloxacin on the QT interval was evaluated in 3 different sessions of the trial. All subjects received moxifloxacin in Session 1 while only those subjects in the placebo/moxifloxacin group received moxifloxacin in Sessions 3 and 5. The placebo subtracted mean changes (90% CI) for moxifloxacin in the three sessions (1, 3 and 5) 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. The lower limit of the 90% confidence interval was greater than zero in the 30 mg dose of solifenacin. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

The effect of solifenacin on QTc interval change in male has not been investigated, and caution should be taken in extrapolating the findings of this study to males.

The pharmacokinetics of solifenacin have not been established in pediatric patients.