Solifenacin PMCS

Solifenacin PMCS is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.

Dosing Information

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

Dose Adjustment in Patients with Renal Impairment

For patients with severe renal impairment (CLcr < 30 mL/min), a daily dose of Solifenacin PMCS greater than 5 mg is not recommended.

Dose Adjustment in Patients with Hepatic Impairment

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

Dose Adjustment in Patients Taking CYP3A4 Inhibitors

When administered with potent CYP3A4 inhibitors such as ketoconazole, a daily dose of Solifenacin PMCS greater than 5 mg is not recommended.

Solifenacin PMCS is contraindicated in patients with:

• urinary retention ,
• gastric retention ,
• uncontrolled narrow-angle glaucoma , and
• in patients who have demonstrated hypersensitivity to the drug.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Angioedema and Anaphylactic Reactions

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.

Urinary Retention

Solifenacin PMCS, like other anticholinergic drugs, should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

Gastrointestinal Disorders

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

Central Nervous System Effects

Solifenacin PMCS is associated with anticholinergic central nervous system (CNS) effects. 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 PMCS affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Controlled Narrow-Angle Glaucoma

Solifenacin PMCS should be used with caution in patients being treated for narrow-angle glaucoma.

Hepatic Impairment

Solifenacin PMCS should be used with caution in patients with hepatic impairment. Doses of Solifenacin PMCS greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin PMCS is not recommended for patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment

Solifenacin PMCS should be used with caution in patients with renal impairment. Doses of Solifenacin PMCS greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min).

Patients with Congenital or Acquired QT Prolongation

In a study of the effect of solifenacin on the QT interval in 76 healthy women 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 PMCS for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Patients should be informed that antimuscarinic agents such as Solifenacin PMCS have been associated with constipation and blurred vision. Patients should be advised to contact their physician if they experience severe abdominal pain or become constipated for 3 or more days. Because Solifenacin PMCS may cause blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effect on the patient's vision has been determined. Heat prostration (due to decreased sweating) can occur when anticholinergic drugs, such as Solifenacin PMCS, are used in a hot environment. Patients should read the patient leaflet entitled “Patient Information Solifenacin PMCS” before starting therapy with Solifenacin PMCS.

Patients should be informed that solifenacin may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue solifenacin therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Use In Specific Populations

Pregnancy

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 PMCS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of Solifenacin PMCS 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.

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 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 PMCS should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue Solifenacin PMCS in nursing mothers.

Pediatric Use

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

Geriatric Use

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 PMCS.

Multiple dose studies of Solifenacin PMCS 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).

Renal Impairment

Solifenacin PMCS 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 PMCS greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min).

Hepatic Impairment

Solifenacin PMCS 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 PMCS greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin PMCS is not recommended for patients with severe hepatic impairment (Child-Pugh C).

Gender

The pharmacokinetics of solifenacin is not significantly influenced by gender.

Clinical Trials Experience

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 PMCS 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 PMCS 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 PMCS 10 mg group. Angioneurotic edema has been reported in one patient taking Solifenacin PMCS 5 mg. Compared to 12 weeks of treatment with Solifenacin PMCS, 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 PMCS 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

Post-Marketing Experience

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, palpitations;

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

Renal:renal impairment;

Metabolism and nutrition disorders: decreased appetite, hyperkalemia;

Dermatologic:exfoliative dermatitis and erythema multiforme;

Eye disorders:glaucoma;

Gastrointestinal disorders:gastroesophageal reflux disease and ileus;

Respiratory, thoracic and mediastinal disorders: dysphonia;

Musculoskeletal and connective tissue disorders: muscular weakness;

Overdosage with Solifenacin PMCS can potentially result in severe anticholinergic effects and should be treated accordingly. The highest dose ingested in an accidental overdose of solifenacin succinate was 280 mg in a 5-hour period. This case was associated with mental status changes. Some cases reported a decrease in the level of consciousness.

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.

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

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 PMCS 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)*

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 PMCS 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 PMCS tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.

Effect of food

Solifenacin PMCS may be administered without regard to meals. A single 10 mg dose administration of Solifenacin PMCS 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 600L.

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.