Soliksa-Xantis (Tablets) Instructions for Use

Marketing Authorization Holder

Xantis Pharma, Limited (Cyprus)

Manufactured By

Saneca Pharmaceuticals, a.s. (Slovakia)

ATC Code

G04BD08 (Solifenacin)

Active Substance

Solifenacin (Rec.INN registered by WHO)

Dosage Forms

	Soliksa-Xantis	Film-coated tablets, 5 mg: 10, 20, 30, 50, 60, 90 or 100 pcs.
		Film-coated tablets, 10 mg: 10, 20, 30, 50, 60, 90 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex.

Excipients: lactose monohydrate – 55.25 mg, corn starch – 15 mg, talc – 1.5 mg, magnesium stearate – 0.75 mg.

Film coating composition opadry yellow OY 32823 – 2 mg (hypromellose 6cP (E464) – 1.25 mg, titanium dioxide (E171) – 0.5688 mg, macrogol 400 – 0.125 mg, iron oxide yellow (E172) – 0.056 mg, iron oxide red (E172) – 0.0002 mg).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Film-coated tablets pink, round, biconvex.

Excipients: lactose monohydrate – 110.5 mg, corn starch – 30 mg, talc – 3 mg, magnesium stearate – 1.5 mg.

Film coating composition opadry white 03B28796 – 3.6 mg (hypromellose 6cP (E464) – 2.25 mg, titanium dioxide (E171) – 1.125 mg, macrogol 400 – 0.225 mg), opadry brown 02F 23883 – 0.4 mg (hypromellose 5 cP (E464) – 0.2374 mg, titanium dioxide (E171) – 0.0895 mg, macrogol 6000 – 0.0475 mg, iron oxide yellow (E172) – 0.0128 mg, iron oxide red (E172) – 0.0128).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Drug reducing the tone of the smooth muscles of the urinary tract

Pharmacotherapeutic Group

Drugs for the treatment of frequent urination and urinary incontinence, antispasmodic agent

Pharmacological Action

Antispasmodic.

Solifenacin is a specific competitive inhibitor of muscarinic receptors, predominantly the M₃ subtype. It has also been established that Solifenacin has low or no affinity for various other receptors and ion channels.

The efficacy of solifenacin at doses of 5 mg and 10 mg in overactive bladder syndrome is observed within the first week of treatment and stabilizes over the subsequent 12 weeks of treatment. The maximum effect may be observed after 4 weeks. Efficacy is maintained with long-term use (at least 12 months).

Pharmacokinetics

After oral administration, C_max in plasma is reached in 3-8 hours. T_max is dose-independent. C_max and AUC increase proportionally with dose escalation from 5 to 40 mg. Absolute bioavailability is 90%. Food intake does not affect the C_max and AUC of solifenacin.

The pharmacokinetics of solifenacin are linear within the therapeutic dose range.

After IV administration, the V_d of solifenacin is about 600 L. The binding of solifenacin to plasma proteins, mainly α₁-acid glycoprotein, is about 98%.

Solifenacin is extensively metabolized in the liver, primarily by the CYP3A4 isoenzyme. However, there are alternative metabolic pathways for solifenacin. The systemic clearance of solifenacin is about 9.5 L/h, and the terminal T_1/2 is 45-68 hours.

Following oral administration of the drug, the following metabolites were identified in plasma besides solifenacin: one pharmacologically active (4R-hydroxysolifenacin) and three inactive (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide of solifenacin).

After a single administration of 10 mg of ¹⁴C-labeled solifenacin, after 26 days about 70% of the radioactivity was detected in the urine and 23% in the feces. In urine, approximately 11% of the radioactivity was found as unchanged active substance, about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide of solifenacin, and 8% as the 4R-hydroxy metabolite (active metabolite).

In patients with mild and moderate renal impairment, the C_max and AUC of solifenacin differ slightly from those in healthy volunteers.

In patients with severe renal impairment (CrCl ≤30 ml/min), the exposure to solifenacin is significantly higher – an increase in C_max of about 30%, AUC of more than 100%, and T_1/2 of more than 60%. A statistically significant correlation was noted between CrCl and the clearance of solifenacin.

In patients with moderate hepatic impairment (7 to 9 points on the Child-Pugh scale), the C_max value does not change, AUC increases by 60%, and T_1/2 doubles. Pharmacokinetics in patients with severe hepatic impairment have not been studied.

Indications

Treatment of urgency (imperative) urinary incontinence, frequent urination, and urgency (imperative) urges to urinate, characteristic of patients with overactive bladder syndrome.

ICD codes

Dosage Regimen

Administer orally with a full glass of water.

Swallow the tablet whole; do not crush, split, or chew.

The recommended initial dose for adults and elderly patients is 5 mg once daily.

If the 5 mg dose is well-tolerated but requires greater efficacy, the dose may be increased to 10 mg once daily.

Do not exceed the maximum daily dose of 10 mg.

Take the tablet at approximately the same time each day, with or without food.

For patients with severe renal impairment (CrCl <30 mL/min), the dose should not exceed 5 mg once daily.

For patients with moderate hepatic impairment (Child-Pugh score 7-9), the dose should not exceed 5 mg once daily.

Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole) requires a maximum dose of 5 mg.

Contraindicated in patients with severe hepatic impairment or severe renal impairment concurrently taking potent CYP3A4 inhibitors.

Discontinue treatment if severe adverse reactions, such as urinary retention or intestinal obstruction, occur.

Re-evaluate therapy periodically for continued need and efficacy.

Adverse Reactions

Most common – dry mouth (11% at a dose of 5 mg/day, 22% at a dose of 10 mg/day, 4% – placebo).

From the digestive system common – constipation, nausea, dyspepsia, abdominal pain; uncommon – gastroesophageal reflux disease, dry throat; rare – intestinal obstruction, coprostasis; very rare – vomiting, decreased appetite.

From the urinary system uncommon – urinary tract infections, difficulty urinating; rare – urinary retention; very rare – renal failure.

From the CNS uncommon – drowsiness, dysgeusia (taste disturbance); very rare – dizziness, headache.

From the organ of vision common – blurred vision (impaired accommodation); uncommon – dry eyes.

From the respiratory system uncommon – dry nasal cavity.

From the skin and subcutaneous tissue uncommon – dry skin; very rare – erythema multiforme, pruritus, rash, urticaria, angioedema, exfoliative dermatitis.

Other uncommon – fatigue, edema of the lower extremities; cannot exclude QT interval prolongation and torsades de pointes type arrhythmias, impaired liver function with increased ALT, AST, GGT activity, cases of hyperkalemia, allergic reactions.

Contraindications

Urinary retention; severe gastrointestinal diseases (including toxic megacolon); myasthenia gravis; closed-angle glaucoma; severe hepatic impairment; severe renal impairment or moderate hepatic impairment with simultaneous treatment with CYP3A4 inhibitors (e.g., ketoconazole); hemodialysis; childhood; hypersensitivity to solifenacin.

Use in Pregnancy and Lactation

Use with caution during pregnancy.

Data on the excretion of solifenacin in human breast milk are not available. Use during breastfeeding is not recommended.

In experimental studies in animals, no direct adverse effects on fertility, embryo/fetal development, or childbirth were identified.

Special Precautions

With caution: clinically significant bladder outlet obstruction with risk of urinary retention; gastrointestinal obstructive diseases (including gastric stasis); risk of reduced gastrointestinal motility; severe renal impairment (CrCl <30 ml/min), moderate hepatic impairment (7-9 points on the Child-Pugh scale) (doses for these patients should not exceed 5 mg); concomitant use of strong CYP3A4 isoenzyme inhibitors, e.g., ketoconazole; hiatal hernia, gastroesophageal reflux, concomitant use with drugs (e.g., bisphosphonates) that may cause or exacerbate esophagitis; peripheral neuropathy; with such risk factors as long QT syndrome and hypokalemia (QT interval prolongation and torsades de pointes type arrhythmias have been observed).

Before starting treatment with solifenacin, other causes of urinary disorders (heart failure or kidney disease) should be ruled out. If a urinary tract infection is detected, appropriate antimicrobial treatment should be initiated.

Effect on ability to drive vehicles and operate machinery

Solifenacin, like other muscarinic receptor antagonists, may cause blurred vision, as well as drowsiness (rarely) and fatigue, which may negatively affect the ability to drive a car and operate machinery. Patients should take precautions when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant treatment with drugs possessing muscarinic receptor blocking properties may result in a more pronounced therapeutic effect and the development of adverse effects. After discontinuation of solifenacin, a one-week break should be made before starting treatment with another muscarinic receptor antagonist. The therapeutic effect may be reduced with the simultaneous use of muscarinic receptor agonists.

Solifenacin may reduce the effect of drugs stimulating gastrointestinal motility, e.g., metoclopramide and cisapride.

Solifenacin is metabolized by CYP3A4. Concomitant administration of ketoconazole at a dose of 200 mg/day, a CYP3A4 inhibitor, caused a twofold increase in the AUC of solifenacin, and at a dose of 400 mg/day – a threefold increase. Therefore, the maximum dose of solifenacin should not exceed 5 mg if the patient is simultaneously taking ketoconazole or therapeutic doses of other CYP3A4 inhibitors (such as ritonavir, nelfinavir, itraconazole). Concomitant use of solifenacin and a CYP3A4 inhibitor is contraindicated in patients with severe renal impairment or with moderate hepatic impairment. Since Solifenacin is metabolized by CYP3A4, pharmacokinetic interaction with other CYP3A4 substrates with higher affinity (verapamil, diltiazem) and with CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.