Solitsin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOLICIN (SOLICIN)

Composition:

Active substance:
solifenacin succinate;

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

Excipients:
lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate;

Film coating
Opadry
yellow
02
F
220022
for 5 mg tablets:
hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide yellow (E 172);

Film coating
Opadry
pink
02
F
240016
for 10 mg tablets:
hypromellose, titanium dioxide (E 171), polyethylene glycol 8000, talc, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form.
Film-coated tablets.

Main physicochemical properties:
5 mg tablets – light yellow, round, biconvex film-coated tablets;

10 mg tablets – light pink, round, biconvex film-coated tablets, with a score line on one side and smooth on the other.

Pharmacotherapeutic group.
Medicinal products used in urology. Medicinal products 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 contracts 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 week 1 of treatment and stabilized over the subsequent 12 weeks of therapy. Open-label studies with long-term use have shown that efficacy is maintained for at least 12 months.

Pharmacokinetics

Absorption.
After tablet intake, maximum plasma concentration (Cmax) of solifenacin is reached within 3–8 hours. Time to maximum concentration (tmax) does not depend on the drug dose. Cmax and area under the plasma concentration-time curve (AUC) increase proportionally with dose escalation from 5 to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect Cmax and 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, mainly by cytochrome P450 3A4 (CYP3A4). Systemic clearance of solifenacin is approximately 9.5 L/hour, and the terminal half-life (t1/2) ranges from 45 to 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 10 mg dose of [14C-labeled] solifenacin, approximately 70% of the radioactive label was recovered in urine and 23% in feces. In urine, approximately 11% of the radioactive label was excreted 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).

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 AUC of solifenacin (5 and 10 mg) was similar in healthy elderly volunteers (aged 65–80 years) and in healthy younger and middle-aged volunteers (< 55 years). The mean absorption rate, expressed as tmax, was slightly lower, and the terminal elimination half-life (t1/2) was approximately 20% longer in elderly patients. These minor differences are not clinically significant.

Pharmacokinetics of solifenacin have not been studied in children and adolescents.

Sex.
Pharmacokinetics of solifenacin are independent of patient sex.

Race.
Race does not influence the pharmacokinetics of solifenacin.

Renal impairment.
AUC and Cmax 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), AUC of solifenacin is significantly higher—Cmax increases by approximately 30%, AUC by over 100%, and elimination half-life (t1/2) 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 7–9), Cmax remains unchanged, AUC increases by 60%, and elimination half-life (t1/2) 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) voiding sensations characteristic of patients with overactive bladder syndrome.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Pharmacological interactions.

Concomitant use of other medicinal products with anticholinergic properties may lead to more pronounced therapeutic and adverse effects. After discontinuation of solifenacin, approximately a one-week interval should be observed before starting treatment with another anticholinergic agent. 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 the isoenzymes CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 isolated from human liver microsomes. Therefore, it is unlikely that solifenacin will alter the clearance of medicinal products metabolized by these CYP enzymes.

Effect of other medicinal products on the pharmacokinetics of solifenacin.

Solifenacin is metabolized by the CYP3A4 isoenzyme. Concomitant administration of ketoconazole (200 mg daily), a strong inhibitor of the CYP3A4 isoenzyme, resulted in a doubling of solifenacin AUC, and at a dose of 400 mg daily, a threefold increase. Therefore, the maximum dose of solifenacin should not exceed 5 mg when administered concomitantly with ketoconazole or therapeutic doses of other strong CYP3A4 isoenzyme inhibitors such as 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 or moderate hepatic impairment.

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

Effect of solifenacin on the pharmacokinetics of medicinal products.

Oral contraceptives.

No pharmacokinetic interaction between solifenacin and combined oral contraceptives (ethinylestradiol/levonorgestrel) was observed.

Warfarin.

Administration of solifenacin does not cause changes in the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time.

Digoxin.

Administration of solifenacin does not affect the pharmacokinetics of digoxin.

Special precautions for use.

Before initiating treatment with solifenacin, it is necessary to rule out other potential causes of frequent urination (such as heart failure or kidney disease). If a urinary tract infection is diagnosed, appropriate antibacterial therapy should be initiated.

The drug should be used with caution in patients:

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

In patients with risk factors such as a history of QT interval prolongation 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 sphincter.

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

There have been several reported cases of angioedema with airway obstruction in patients taking solifenacin. Therefore, if angioedema occurs, solifenacin should be discontinued immediately and appropriate measures taken or necessary treatment initiated.

Anaphylactic reactions have been observed in some patients receiving solifenacin succinate. If an anaphylactic reaction occurs, solifenacin should be discontinued and appropriate measures taken or appropriate treatment initiated.

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

Use during pregnancy or breastfeeding.

Pregnancy.

There are no clinical data on women who became pregnant while using solifenacin. Animal studies have not shown any direct adverse effects on fertility, embryonic/fetal development, or delivery. The potential risk is unknown. Caution should be exercised when prescribing this drug to pregnant women.

Breastfeeding period.

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

Ability to influence reaction rate while driving or operating machinery.

Since solifenacin, like other anticholinergic drugs, may cause blurred vision and, rarely, somnolence and fatigue (see section "Adverse reactions"), taking the drug may negatively affect the ability to drive or operate machinery.

Method of Administration and Dosage

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: Dosage adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), solifenacin should be administered with caution and not exceed 5 mg once daily (see section "Pharmacokinetics").

Patients with hepatic impairment: Dosage adjustment is not required in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the drug should be used with caution 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 strong inhibitors of the CYP3A4 isoenzyme, such as ritonavir, nelfinavir, or itraconazole (see section "Interaction with other medicinal products and other types of interactions").

The medicinal product should be taken orally, swallowing the tablets whole with liquid, regardless of food intake.

Children.

The safety and efficacy of solifenacin in children have not been established; therefore, the drug should not be used in pediatric patients.

Overdose.

Symptoms.

Overdose of solifenacin succinate may lead to severe anticholinergic effects. The highest dose of solifenacin succinate accidentally taken by one patient was 280 mg within 5 hours, which resulted in altered mental status but did not require hospitalization.

Treatment. In case of solifenacin succinate overdose, activated charcoal should be administered. Gastric lavage is effective if performed within one hour, but emesis should not be induced.

As with overdose of other anticholinergic agents, symptoms should be managed as follows:

• For severe central anticholinergic effects (hallucinations, pronounced agitation) – physostigmine or carbachol;
• For seizures or pronounced agitation – benzodiazepines;
• For respiratory insufficiency – artificial ventilation of the lungs;
• For tachycardia – beta-blockers;
• For acute urinary retention – catheterization;
• For mydriasis – instillation of pilocarpine into the eyes and/or dimming the room where the patient is located.

As with overdose of other anticholinergic drugs, special attention should be paid to patients with established risk factors for QT interval prolongation (i.e., hypokalemia, bradycardia, and concomitant use of drugs that prolong the QT interval) and patients with previously diagnosed 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 usually mild or moderate in severity. The frequency of these effects depends on the dose of the medicinal product.

The most common adverse effect is dry mouth. The intensity of dry mouth is usually mild and has led to discontinuation of treatment only in isolated cases.

The following frequency categories were used to assess adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Infections and infestations.

Uncommon: urinary tract infections, cystitis.

Immune system.

Frequency not known: anaphylactic reaction.

Metabolism and nutrition disorders.

Frequency not known: decreased appetite, hyperkalemia.

Psychiatric disorders.

Very rare: hallucinations, confusion.

Frequency not known: delirium.

Nervous system.

Uncommon: somnolence, taste disturbance.

Rare: dizziness, headache.

Eye disorders.

Common: blurred vision.

Uncommon: dry eyes.

Frequency not known: glaucoma.

Cardiac disorders.

Frequency not known: torsade de pointes, QT interval prolongation on electrocardiogram, atrial fibrillation, palpitations, tachycardia.

Respiratory system.

Uncommon: dryness of the nasal mucosa.

Frequency not known: dysphonia.

Gastrointestinal disorders.

Very common: dry mouth.

Common: constipation, nausea, dyspepsia, abdominal pain.

Uncommon: gastroesophageal reflux, dry throat.

Rare: colonic obstruction, fecal impaction, vomiting.

Frequency not known: intestinal obstruction, abdominal discomfort.

Hepatobiliary disorders.

Frequency not known: liver function abnormalities, abnormalities in laboratory tests of liver function.

Skin and subcutaneous tissue disorders.

Uncommon: dry skin.

Rare: pruritus, rash.

Very rare: erythema multiforme, urticaria, angioedema.

Frequency not known: exfoliative dermatitis*.

Musculoskeletal and connective tissue disorders.

Frequency not known: muscle weakness.

Renal and urinary disorders.

Uncommon: difficulty in urination.

Rare: urinary retention.

Frequency not known: renal failure.

General disorders and administration site conditions.

Uncommon: increased fatigue, peripheral edema.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister, 1 blister in a carton.

10 tablets in a blister, 3 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Public joint-stock company "Scientific and Production Center "Borys Hrinchenko Kyiv University Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.