Solifenacin

Solifenacin is an Anticholinergic Agent belonging to pharmacology class of Urinary antispasmodics.

Solifenacin can be used in the treatment of Neurogenic detrusor overactivity and Overactive bladder.

Solifenacin is absorbed from the gastrointestinal tract with bioavailability of approx 90% and Plasma protein binding of approx 98%, mainly to α₁-acid glycoprotein which gets extensively metabolised in the liver, mainly by the CYP3A4 isoenzyme, but alternative metabolic pathways may also contribute; metabolism via N-oxidation and 4R-hydroxylation forms 1 active metabolite (4R-hydroxy solifenacin) and 3 inactive metabolites (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide solifenacin) and get excreted via urine (approx 70%; approx 11% as unchanged drug, 8% as the active metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, 18% as the N-oxide metabolite); faeces (23%). Terminal elimination half-life: 45-68 hours (adults); approx 26 hours (children).

The common side effects of Solifenacin includes: QT prolongation and torsades de pointes (particularly in patients with known risk factors), CNS effects (e.g. headache, confusion, hallucinations, somnolence), heat prostration (in presence of high environmental temperature)..

Solifenacin is available in the form of Tablet and Suspension

The molecule is available in India, Japan, Germany, China.

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.

Tmax of Solifenacin was 3-8 hours (tablet); 4-12 hours (oral suspension).

Solifenacin is available in Tablet and Suspension

Oral suspension: Shake well before use. Administer liquid (water or milk) after administration; simultaneous administration of food or liquid may result in bitter taste. Administer with an accurate measuring device, such as an oral syringe.

Tablet: Administer tablet with water without regard to food. Swallow whole. Do not crush or chew.

Solifenacin can be used in the treatment of Neurogenic detrusor overactivity and Overactive bladder.

Solifenacin inhibits muscarinic receptors resulting in decreased urinary bladder contraction, increased residual urine volume, and decreased detrusor muscle pressure.

Solifenacin is approved for use in the following clinical indications:

Neurogenic detrusor overactivity: Treatment of neurogenic detrusor overactivity in pediatric patients ≥2 years of age.

Overactive bladder: Treatment of overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence in adults.

Overactive bladder: Oral: Initial: 5 mg once daily; if tolerated, may increase to 10 mg once daily.

Missed doses: Oral suspension: Administer as soon as possible as long as ≤12 hours have passed. If >12 hours have passed, skip dose and administer next dose at usual time.

5 mg/5ml; 5mg, 10 mg

Tablet and Suspension.

• Dose Adjustment in Kidney Patient:

CrCl ≥30 mL/minute: There are no dosage adjustments

CrCl <30 mL/minute: Maximum dose: 5 mg/day

• Dose Adjustment in Hepatic Patient:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary; use with caution.

Moderate impairment (Child-Pugh class B): Maximum dose: 5 mg/day.

Severe impairment (Child-Pugh class C): Use is not recommended.

• Dose Adjustment in Pediatric Patient:

Neurogenic detrusor overactivity : Children ≥2 years and Adolescents:

Oral suspension (1 mg/mL):

• 9 to 15 kg: Oral: Initial dose: 2 mg once daily; may titrate every 3 weeks to lowest effective dose. Maximum daily dose: 4 mg/day.
• >15 to 30 kg: Oral: Initial dose: 3 mg once daily; may titrate every 3 weeks to lowest effective dose. Maximum daily dose: 5 mg/day.
• >30 to 45 kg: Oral: Initial dose: 3 mg once daily; may titrate every 3 weeks to lowest effective dose. Maximum daily dose: 6 mg/day.
• >45 to 60 kg: Initial dose: Oral: 4 mg once daily; may titrate every 3 weeks to lowest effective dose. Maximum daily dose: 8 mg/day.
• >60 kg: Initial dose: Oral: 5 mg once daily; may titrate every 3 weeks to lowest effective dose. Maximum daily dose: 10 mg/day.

Solifenacin may be contraindicated in the following conditions:-

Myasthenia gravis, uncontrolled narrow-angle glaucoma , severe gastrointestinal condition (e.g. toxic megacolon, gastric retention); urinary retention (when used for overactive bladder). Patient undergoing haemodialysis. Severe hepatic impairment (Child-Pugh class C). Concomitant use with strong CYP3A4 inhibitors in patients with severe renal or moderate hepatic impairment.

Concerns related to adverse effects:

• Angioedema: Potentially life-threatening angioedema involving the face, lips, tongue, and/or larynx have been reported; some cases have occurred after the first dose.

• CNS effects: CNS effects have been reported (eg, headache, confusion, hallucinations, somnolence, dementia) (Dantas 2022; Malcher 2022, manufacturer’s labeling). May cause drowsiness and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Heat prostration: May occur in the presence of increased environmental temperature; use caution in hot weather and/or exercise.

• Hypersensitivity reactions: Anaphylactic reactions have been reported rarely; may be life-threatening.

Disease-related concerns:

• Alzheimer disease: Preliminary data suggest that long-term use of anticholinergics may potentially adversely affect the clinical course of Alzheimer disease in patients receiving cholinesterase inhibitors.

• Bladder outlet obstruction: Use not recommended in patients with significant bladder outlet obstruction (eg, BPH) being treated for overactive bladder; may increase the risk of urinary retention.

• Gastrointestinal disease: Use with caution in patients with decreased GI motility (severe constipation, ulcerative colitis) or GI obstructive disorders (pyloric stenosis); may increase the risk of gastric retention. Instruct patients to report severe abdominal pain or constipation that lasts longer than 3 days.

• Glaucoma: Use with caution in patients with controlled (treated) narrow-angle glaucoma; use is contraindicated in uncontrolled narrow-angle glaucoma.

• Hepatic impairment: Use with caution in patients with moderate hepatic impairment (Child-Pugh class B); dosage adjustment required; use is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

• QT prolongation: Use with caution in patients with a known history of QT prolongation or other risk factors for QT prolongation (eg, concomitant use of medications known to prolong QT interval, electrolyte abnormalities). The risk for QT prolongation is dose-related.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required for severe renal impairment (CrCl <30 mL/minute).

There is no sufficient scientific evidence traceable regarding use and safety of Solifenacin in concurrent use with alcohol.

It is not known if solifenacin is present in breast milk.

Pregnancy Category (FDA): 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.

Grapefruit juice may increase the serum level effects of solifenacin. Management: Monitor closely with concurrent use.

The adverse reactions related to Solifenacin can be categorized as

Common Adverse effects:

QT prolongation and torsades de pointes (particularly in patients with known risk factors), CNS effects (e.g. headache, confusion, hallucinations, somnolence), heat prostration (in presence of high environmental temperature).

Less Common Adverse effects:

Faecal impaction, colonic obstruction, intestinal obstruction; urinary retention.

Rare Adverse effects:

Neuralgia, peripheral neuropathy, sciatica.

The clinically relevant drug interactions of Solifenacin is briefly summarized here

• Increased plasma concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, nelfinavir, itraconazole).
• May enhance the therapeutic effects and adverse reactions when used concomitantly with other agents with anticholinergic activity; an interval of approx 1 week between using these drugs is recommended.
• May reduce efficacy with cholinergic receptor agonists.
• Efficacy of drugs that stimulate gastrointestinal motility (e.g. metoclopramide, cisapride) may be reduced by solifenacin.

The most common side effects of Solifenacin includes: QT prolongation and torsades de pointes (particularly in patients with known risk factors), CNS effects (e.g. headache, confusion, hallucinations, somnolence), heat prostration (in presence of high environmental temperature).

Pregnancy

Pregnancy Category (FDA): 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.

Labor and Delivery

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

Pediatric Use

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

Geriatic 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. 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).

Gender

The pharmacokinetics of solifenacin is not significantly influenced by gender.

Race

There is no FDA guidance on the use of Solifenacin with respect to specific racial populations.

Renal Impairment

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)

Hepatic Impairment

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)

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Solifenacin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Solifenacin in patients who are immunocompromised.

Symptoms: Severe anticholinergic effects (e.g. blurred vision, fixed and dilated pupils, tremors, dry skin).

Management: Symptomatic and supportive treatment. Administer activated charcoal. Perform gastric lavage within 1 hour of ingestion but vomiting must not be induced. Give physostigmine or carbachol to treat hallucinations or pronounced excitation; benzodiazepines for convulsions; β-blockers for tachycardia. Administer pilocarpine eye drops and/or place the patient in a dark room in case of mydriasis. Employ artificial respiration during respiratory insufficiency and catheterization for urinary retention. Monitor ECG as necessary.

Pharmacodynamics:

Solifenacin is a selective, competitive inhibitor of the muscarinic M₃ subtype receptor, which causes a decrease in urinary bladder contraction and detrusor muscle pressure, and an increase in residual urine volume..

Pharmacokinetics:

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

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

1. https://www.uptodate.com/contents/ Solifenacin -drug-information?search= Solifenacin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Solifenacin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Solifenacin ?type=full&mtype=generic#mechanism-of-action