Solifur

I N S T R U C T I O N for medical use of the medicinal product SOLIFUR®

Composition:

active substance: solifenacin succinate;

1 tablet contains 5 mg or 10 mg of solifenacin succinate;

excipients: lactose, hypromellose (6 mPa·s), magnesium stearate, pregelatinized corn starch, magnesium stearate;

coating composition: Opadry Pink 03F14895 (hypromellose (6 mPa·s), talc, titanium dioxide (E 171), polyethylene glycol 8000, iron(III) oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round film-coated tablets of light pink to pink color.

Pharmacotherapeutic group. Medicinal products used in urology. Drugs for the treatment of frequent urination and urinary incontinence. ATC code G04BD08.

Pharmacological Properties

Pharmacodynamics

Solifenacin is a competitive, specific antagonist of cholinergic receptors. The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine induces contraction of the detrusor smooth muscle by acting on muscarinic receptors, predominantly of the M3 subtype.

In vitro and in vivo studies have demonstrated that solifenacin is a competitive, specific antagonist of cholinergic receptors, primarily of the M3 subtype. It has also been established that solifenacin has weak or no affinity for other receptors and tested ion channels.

The efficacy of the drug, evaluated in several double-blind, randomized, controlled clinical trials in men and women with overactive bladder syndrome, was observed as early as the first week of treatment and stabilized over the subsequent 12 weeks of therapy. Open-label long-term studies have shown that efficacy is maintained for at least 12 months.

Pharmacokinetics

Absorption. After tablet administration, maximum plasma concentration (Cmax) of solifenacin is reached within 3–8 hours. The time to reach maximum concentration (tmax) is independent of the drug dose. Cmax and area under the curve (AUC) increase proportionally with doses ranging from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect Cmax or AUC values of solifenacin.

Distribution. Solifenacin is highly bound (approximately 98%) to plasma proteins, primarily to α1-acid glycoprotein.

Metabolism. Solifenacin is extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). Systemic clearance of solifenacin is approximately 9.5 L/hour, and its terminal half-life ranges from 45–68 hours. After oral administration, in addition to solifenacin, one pharmacologically active metabolite (4R-hydroxysolifenacin) and three inactive metabolites (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide of solifenacin) have been identified in plasma.

Excretion. After a single dose of 10 mg [14C-labeled] solifenacin, approximately 70% of the radioactive label is excreted in urine and 23% in feces. In urine, approximately 11% of the radioactive label is excreted as unchanged active substance; approximately 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxy metabolite (active metabolite).

Dose dependency. Within the therapeutic dose range, the pharmacokinetics of the drug are linear.

Pharmacokinetic characteristics in specific patient populations.

Age. Dose adjustment based on age is not necessary. Studies have shown that solifenacin exposure (5 and 10 mg), expressed as AUC, is similar in healthy elderly volunteers (aged 65 to 80 years) and healthy younger and middle-aged volunteers (< 55 years). The mean absorption rate, expressed as tmax, was slightly lower, and the terminal elimination half-life was approximately 20% longer in elderly patients. These minor differences are not clinically significant.

The pharmacokinetics of solifenacin have not been studied in children and adolescents.

Gender. The pharmacokinetics of solifenacin are not influenced by patient gender.

Race. Race does not affect the pharmacokinetics of solifenacin.

Renal impairment. Cmax and AUC of solifenacin in patients with mild to moderate renal impairment are slightly different from those in healthy volunteers. In patients with severe renal impairment (creatinine clearance < 30 mL/min), solifenacin exposure is significantly higher—Cmax increases by approximately 30%, AUC by over 100%, and elimination half-life by over 60%. A statistically significant correlation between creatinine clearance and solifenacin clearance has been observed. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Hepatic impairment. In patients with moderate hepatic impairment (Child–Pugh score of 7 to 9), Cmax remains unchanged, AUC increases by 60%, and elimination half-life doubles. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

Symptomatic treatment of urgency (imperative) urinary incontinence and/or frequent urination, as well as urgency (imperative) urination urges typical for patients with overactive bladder syndrome.

Contraindications.

The drug is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients; in patients with urinary retention, severe gastrointestinal disorders (including toxic megacolon), myasthenia gravis, or angle-closure glaucoma, as well as in patients at risk of developing these conditions; during hemodialysis (see section "Pharmacokinetics"); in severe hepatic impairment (see section "Pharmacokinetics"); in patients with severe renal impairment or moderate hepatic impairment who are being treated with strong inhibitors of cytochrome CYP3A4, such as ketoconazole (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other types of interactions.

Pharmacological interactions.

Concomitant use of other medicinal products with anticholinergic properties may result in enhanced therapeutic and adverse effects. After discontinuation of solifenacin, approximately a one-week interval should be maintained before starting other anticholinergic therapies. The therapeutic effect of solifenacin may be reduced when used concomitantly with cholinergic receptor agonists. Solifenacin may reduce the effect of medicinal products that stimulate gastrointestinal motility, such as metoclopramide and cisapride.

Pharmacokinetic interactions.

In vitro studies have shown that solifenacin, at therapeutic concentrations, does not inhibit liver microsomal CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 enzymes. Therefore, it is unlikely that solifenacin affects the clearance of drugs metabolized by these CYP enzymes.

Effect of other medicinal products on the pharmacokinetics of solifenacin.

Solifenacin is metabolized by the CYP3A4 enzyme. Concomitant administration of ketoconazole (200 mg/day), a strong inhibitor of CYP3A4, resulted in a doubling of solifenacin AUC, while ketoconazole at a dose of 400 mg/day caused a threefold increase in solifenacin AUC. Therefore, the maximum dose of solifenacin should be limited to 5 mg when administered concomitantly with ketoconazole or therapeutic doses of other potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, nelfinavir, itraconazole) (see section "Dosage and administration").

Concomitant use of solifenacin and a strong inhibitor of the CYP3A4 enzyme is contraindicated in patients with severe renal impairment or moderate hepatic impairment.

The effect of enzyme inducers on the pharmacokinetics of solifenacin and its metabolites, as well as the effect of high-affinity CYP3A4 substrates and their metabolites on solifenacin exposure, has not been studied. Since solifenacin is metabolized by the CYP3A4 enzyme, pharmacokinetic interactions are possible with other substrates of this enzyme that have high affinity (e.g., verapamil, diltiazem) and with CYP3A4 enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of medicinal products.

Oral contraceptives.

Administration of the drug does not affect the pharmacokinetic interaction of solifenacin with combined oral contraceptives (ethinylestradiol/levonorgestrel).

Warfarin.

Administration of the drug does not affect the pharmacokinetic interaction of R-warfarin or S-warfarin or its effect on prothrombin time.

Digoxin.

Administration of the drug does not affect the pharmacokinetics of digoxin.

Special precautions for use.

Before initiating treatment with the drug, the likelihood of other causes of frequent urination (heart failure or kidney disease) should be assessed. If a urinary tract infection is identified, appropriate antibacterial therapy should be initiated.

The drug should be used with caution in patients:

• with clinically significant obstruction of the bladder outlet, which may lead to risk of urinary retention;
• with gastrointestinal obstructive disorders;
• at risk of reduced gastrointestinal motility;
• with severe renal (creatinine clearance < 30 mL/min) and moderate hepatic (Child–Pugh score from 7 to 9) impairment (see sections "Dosage and administration" and "Pharmacokinetics"); doses for these patients should not exceed 5 mg;
• receiving concomitant strong CYP3A4 inhibitors, such as ketoconazole (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction");
• with hiatal hernia and/or gastroesophageal reflux and/or those concurrently taking medications (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

In patients with risk factors such as previously documented QT interval prolongation syndrome and hypokalemia, QT interval prolongation and ventricular tachycardia (torsade de pointes) have been observed.

The safety and efficacy of the drug have not been studied in patients with increased activity of the neurogenic origin urethral sphincter.

Patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

In some patients treated with solifenacin succinate, angioedema with airway obstruction has been reported. If angioedema (Quincke's edema) occurs, treatment with solifenacin succinate should be discontinued and appropriate measures taken or appropriate therapy initiated.

In some patients treated with solifenacin succinate, anaphylactic reactions have been observed. If anaphylactic reactions occur, treatment with solifenacin succinate should be discontinued and appropriate measures taken or appropriate therapy initiated.

The maximum effect of the drug is achieved no earlier than 4 weeks after initiation of treatment.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data in women who became pregnant during treatment with solifenacin. Animal studies have not revealed direct adverse effects on fertility, embryonic/fetal development, or delivery. The potential risk is unknown. Caution should be exercised when administering this drug to pregnant women.

Breastfeeding.

There are no data on the excretion of solifenacin into breast milk. In mice, solifenacin and/or its metabolites pass into milk and cause dose-dependent growth deficiency in newborn mice. Solifenacin use is not recommended during breastfeeding.

Ability to affect reaction rate while driving or operating machinery.

Since solifenacin, like other anticholinergic drugs, may cause blurred vision and, less frequently, somnolence and increased fatigue (see section "Side effects"), taking the drug may negatively affect the ability to drive a vehicle or operate machinery.

Dosage and Administration.

Adults, including elderly patients: The recommended dose is 5 mg of the drug once daily. If necessary, the dose may be increased to 10 mg once daily.

Patients with renal impairment: Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). The drug should be used with caution in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) at a dose not exceeding 5 mg once daily (see section "Pharmacokinetics").

Patients with hepatic impairment: Dose adjustment is not required in patients with mild hepatic impairment. The drug should be used with caution in patients with moderate hepatic impairment (Child–Pugh score 7–9), and the dose should not exceed 5 mg once daily (see section "Pharmacokinetics").

When using strong inhibitors of cytochrome P450 3A4: The maximum dose of the drug should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent inhibitors of cytochrome CYP3A4 isoenzymes, such as ritonavir, nelfinavir, and itraconazole (see section "Interaction with other medicinal products and other forms of interaction").

The drug should be administered orally; tablets should be swallowed whole with liquid, regardless of food intake.

Children.

Safety and efficacy of the drug in children have not been established; therefore, solifenacin should not be prescribed to this patient group.

Overdose.

Symptoms.

Overdose of solifenacin succinate may lead to severe anticholinergic effects. The highest accidental dose of solifenacin succinate reported in a single patient was 280 mg within 5 hours, resulting in mental status changes that did not require hospitalization.

Treatment.

In case of solifenacin succinate overdose, activated charcoal should be administered. Gastric lavage may be beneficial if performed within 1 hour after drug intake; however, emesis should not be induced.

Management of other anticholinergic effects should include:

• severe central nervous system anticholinergic effects such as hallucinations or increased agitation: treatment with physostigmine or carbachol;
• seizures or increased agitation: treatment with benzodiazepines;
• respiratory insufficiency: treatment with artificial ventilation;
• tachycardia: treatment with beta-blockers;
• urinary retention: treatment with catheterization;
• mydriasis: treatment with ophthalmic drops, e.g. pilocarpine, and/or placing the patient in a dark room.

As with overdose of other anticholinergic agents, special attention should be paid to patients with established risk factors for QT interval prolongation (e.g. hypokalemia, bradycardia, concomitant use of drugs that cause QT prolongation) and patients with cardiac diseases (myocardial ischemia, arrhythmias, congestive heart failure).

Adverse reactions.

The medicinal product may cause adverse effects associated with the anticholinergic action of solifenacin, which are generally mild or moderate. Their frequency depends on the dose of the drug.

The most common adverse effect is dry mouth, which was observed in 11% of patients receiving a 5 mg daily dose, in 22% of patients receiving 10 mg daily, and in 4% of those receiving placebo. The severity of dry mouth was generally mild, and led to discontinuation of treatment only in isolated cases. Overall, the medicinal product was well tolerated (approximately 99%), and about 90% of patients continued taking the drug throughout the entire study period of 12 weeks.

The table below lists other adverse effects recorded during clinical trials and in the post-marketing period.

*Post-registration period.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

No special storage conditions required.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratorios Medicamentales Internacionales, S.A.

Manufacturer's address and place of business.

Calle Solana, 26, Torrejón de Ardoz, 28850, Madrid, Spain.

Marketing Authorization Holder.

Esparma GmbH.

Address of the Marketing Authorization Holder.

Bielefelder Strasse 1, 39171 Süpplingen, Germany.