Each film coated tablet contains: Solifenacin succinate 5 mg.
Each film coated tablet contains: Solifenacin succinate 10 mg.
Excipients/Inactive Ingredients: Calcium phosphate dihydrate powder, Lactose monohydrate, Pregelatinized starch (National 78-1551), Edetate disodium, Sodium metabisulfite, Povidone (PVK-30), Butylated hydroxytoluene, Croscarmellose sodium, Colloidal silicon dioxide (Aerosil 200), Magnesium stearate, Hypromellose (HPMC 2910), Propylene glycol, Ethylene glycol & vinyl alcohol graft copolymer (Kollicoat IR), Titanium dioxide (C.I. No.77891), Talc.
5 mg: Iron oxide yellow (C.I. No. 77942).
10 mg: Iron oxide red (C.I. No. 77941) and Polyethylene glycol (PEG 6000).
Pharmacology: Solifenacin is a competitive, specific cholinergic-receptor antagonist.
The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle through muscarinic receptors of which the M3 subtype is predominantly involved. In vitro and in vivo pharmacological studies indicate that Solifenacin is a competitive inhibitor of the muscarinic M3 subtype receptor. In addition, Solifenacin showed to be a specific antagonist for muscarinic receptors by displaying low or no affinity for various other receptors and ion channels tested.
Pharmacokinetics: Absorption: After intake of Solifenacin, maximum Solifenacin plasma concentrations (Cmax) are reached after 3 to 8 hours. 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.
Distribution: 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-acid glycoprotein.
Biotransformation: Solifenacin is extensively metabolized by the liver, primarily by cytochrome P450 3A4 (CYP3A4). However, alternative metabolic pathways exist, that can contribute to the metabolism of Solifenacin. The systemic clearance of Solifenacin is about 9.5 L/h and the terminal half life of solifenacin is 45-68 hours. After oral dosing, one pharmacologically active (4R-hydroxy Solifenacin) and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of Solifenacin) have been identified in plasma in addition to Solifenacin.
Elimination: After a single administration of 10 mg [14C-labelled]-Solifenacin, about 70% of the radioactivity was detected in urine and 23% in feces 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-hydroxy-N-oxide metabolite and 8% as the 4R-hydroxy metabolite (active metabolite).
Other special populations: Renal impairment: The AUC and Cmax of Solifenacin in mild and moderate renally impaired patients, was not significantly different from that found in healthy volunteers. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) exposure to Solifenacin was significantly greater than in the controls with increases in Cmax of about 30%, AUC of more than 100% and t½ of more than 60%. A statistically significant relationship was observed between creatinine clearance and Solifenacin clearance.
Pharmacokinetics in patients undergoing hemodialysis have not been studied.
Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) the Cmax is not affected, AUC increased with 60% and t½ doubled.
Pharmacokinetics of Solifenacin in patients with severe hepatic impairment have not been studied.
Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome.
Posology: Adults, including the elderly: The recommended dose is 5 mg Solifenacin succinate once daily. If needed, the dose may be increased to 10 mg Solifenacin succinate once daily.
Pediatric population: The safety and efficacy of Solifenacin succinate in children have not yet been established. Therefore, Solifenacin succinate should not be used in children.
Patients with renal impairment: No dose adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) should be treated with caution and receive no more than 5 mg once daily.
Patients with hepatic impairment: No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) should be treated with caution and receive no more than 5 mg once daily.
Potent inhibitors of cytochrome P450 3A4: The maximum dose of Solifenacin succinate should be limited to 5 mg when treated simultaneously with Ketoconazole or therapeutic doses of other potent CYP3A4-inhibitors e.g. Ritonavir, Nelfinavir, Itraconazole.
Symptoms: Overdosage with Solifenacin succinate can potentially result in severe anticholinergic effects. 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 not requiring hospitalization.
Treatment: In the event of overdose with Solifenacin succinate the patient should be treated with activated charcoal. Gastric lavage is useful if performed within 1 hour, but vomiting should not be induced.
As for other anticholinergics, symptoms can be treated as follows: Severe central anticholinergic effects such as hallucinations or pronounced excitation: treat with Physostigmine or Carbachol.
Convulsions or pronounced excitation: treat with benzodiazepines.
Respiratory insufficiency: treat with artificial respiration.
Tachycardia: treat with beta-blockers.
Urinary retention: treat with catheterization.
Mydriasis: treat with Pilocarpine eye drops and/or place patient in dark room.
As with other antimuscarinics, in case of overdosing, specific attention should be paid to patients with known risk for QT-prolongation (i.e. hypokalemia, bradycardia and concurrent administration of medicinal products known to prolong QT-interval) and relevant pre-existing cardiac diseases (i.e. myocardial ischemia, arrhythmia, congestive heart failure).
Solifenacin is contraindicated in patients with urinary retention, severe gastro-intestinal condition (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and in patients at risk for these conditions: Patients hypersensitive to the active substance or to any of the excipients.
Patients undergoing hemodialysis.
Patients with severe hepatic impairment.
Patients with severe renal impairment or moderate hepatic impairment and who are on treatment with a potent CYP3A4 inhibitor, e.g. Ketoconazole.
Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Solifenacin succinate. If urinary tract infection is present, an appropriate antibacterial therapy should be started.
Solifenacin succinate should be used with caution in patients with: clinically significant bladder outflow obstruction at risk of urinary retention; gastrointestinal obstructive disorders; risk of decreased gastrointestinal motility; severe renal impairment (creatinine clearance ≤ 30 mL/min), and doses should not exceed 5 mg for these patients; moderate hepatic impairment (Child-Pugh score of 7 to 9), and doses should not exceed 5 mg for these patients; concomitant use of a potent CYP3A4 inhibitor, e.g. Ketoconazole; hiatus hernia/gastro-esophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate esophagitis; autonomic neuropathy.
QT prolongation and Torsade de Pointes have been observed in patients with risk factors, such as pre-existing long QT syndrome and hypokalemia.
Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor overactivity.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Angioedema with airway obstruction has been reported in some patients on Solifenacin succinate. If angioedema occurs, Solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.
Anaphylactic reaction has been reported in some patients treated with Solifenacin succinate. In patients who develop anaphylactic reactions, Solifenacin should be discontinued and appropriate therapy and/or measures should be taken.
The maximum effect of Solifenacin succinate can be determined after 4 weeks at the earliest.
Effects on Ability to Drive and Use Machine: Since Solifenacin, like other anticholinergics may cause blurred vision, and, uncommonly, somnolence and fatigue, the ability to drive and use machines may be negatively affected.
Pregnancy: No clinical data are available from women who became pregnant while taking Solifenacin. Animal studies do not indicate direct harmful effects on fertility, embryonal/fetal development or parturition. The potential risk for humans is unknown. Caution should be exercised when prescribing to pregnant women.
Breastfeeding: No data on the excretion of Solifenacin in human milk are available. In mice, Solifenacin and/or its metabolites was excreted in milk, and caused a dose dependent failure to thrive in neonatal mice. The use of Solifenacin should therefore be avoided during breastfeeding.
Summary of the safety profile:
Due to the pharmacological effect of Solifenacin, Solifenacin succinate may cause anticholinergic undesirable effects of (in general) mild or moderate severity. The frequency of anticholinergic undesirable effects is dose related.
The most commonly reported adverse reaction with Solifenacin succinate was dry mouth. It occurred in 11% of patients treated with 5 mg once daily, in 22% of patients treated with 10 mg once daily and in 4% of placebo-treated patients. The severity of dry mouth was generally mild and did only occasionally lead to discontinuation of treatment. In general, medicinal product compliance was very high (approximately 99%) and approximately 90% of the patients treated with Solifenacin succinate completed the full study period of 12 weeks treatment.
Tabulated list of adverse reactions: (See table.)
Click on icon to see table/diagram/image
Pharmacological interactions: Concomitant medication with other medicinal products with anticholinergic properties may result in more pronounced therapeutic effects and undesirable effects. An interval of approximately one week should be allowed after stopping treatment with Solifenacin succinate, before commencing other anticholinergic therapy. The therapeutic effect of Solifenacin may be reduced by concomitant administration of cholinergic receptor agonists.
Solifenacin can reduce the effect of medicinal products that stimulate the motility of the gastro-intestinal tract, such as Metoclopramide and Cisapride.
Pharmacokinetic interactions: In vitro studies have demonstrated that at therapeutic concentrations, Solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes. Therefore, Solifenacin is unlikely to alter the clearance of drugs metabolized by these CYP enzymes.
Effect of other medicinal products on the pharmacokinetics of Solifenacin: Solifenacin is metabolized by CYP3A4. Simultaneous administration of Ketoconazole (200 mg/day), a potent CYP3A4 inhibitor, resulted in a two-fold increase of the AUC of Solifenacin, while Ketoconazole at a dose of 400 mg/day resulted in a three-fold increase of the AUC of Solifenacin. Therefore, the maximum dose of Solifenacin succinate should be restricted to 5 mg, when used simultaneously with Ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors (e.g. Ritonavir, Nelfinavir, Itraconazole). Simultaneous treatment of Solifenacin and a potent CYP3A4 inhibitor is contraindicated in patients with severe renal impairment or moderate hepatic impairment.
The effects of enzyme induction on the pharmacokinetics of Solifenacin and its metabolites have not been studied as well as the effect of higher affinity CYP3A4 substrates on Solifenacin exposure. Since Solifenacin is metabolized by CYP3A4, pharmacokinetic interactions are possible with other CYP3A4 substrates with higher affinity (e.g. Verapamil, Diltiazem) and CYP3A4 inducers (e.g. Rifampicin, Phenytoin, Carbamazepin).
Effect of Solifenacin on the pharmacokinetics of other medicinal products: Oral Contraceptives: Intake of Solifenacin succinate showed no pharmacokinetic interaction of Solifenacin on combined oral contraceptives (Ethinylestradiol/Levonorgestrel).
Warfarin: Intake of Solifenacin succinate did not alter the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time.
Digoxin: Intake of Solifenacin succinate showed no effect on the pharmacokinetics of Digoxin.
Store at temperature not more than 30°C.
G04BD08 - solifenacin ; Belongs to the class of urinary antispasmodics.
FC tab 5 mg x 3 x 10's. 10 mg x 3 x 10's.