Nigisem

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

Composition:

Active substance: solifenacin succinate;

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

Excipients: lactose monohydrate; maize starch; hypromellose (hydroxypropylmethylcellulose); magnesium stearate;

Coating for 5 mg tablets: Opadry II Yellow film-coating mixture: lactose monohydrate; hypromellose (hydroxypropylmethylcellulose); polyethylene glycol (macrogol); titanium dioxide (E 171); triacetin; iron oxide yellow (E 172);

Coating for 10 mg tablets: Opadry Pink film-coating mixture: talc; hypromellose (hydroxypropylmethylcellulose); polyethylene glycol (macrogol); titanium dioxide (E 171); iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 5 mg tablets: light yellow, round, biconvex film-coated tablets;

for 10 mg tablets: light pink, round, biconvex film-coated tablets.

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 induces contraction of the detrusor smooth muscles 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 following 12 weeks of therapy. In open-label studies with long-term use, efficacy has been maintained for at least 12 months.

Pharmacokinetics

Absorption. After oral administration of tablets, 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 plasma concentration-time curve (AUC) increase proportionally with doses ranging from 5 mg 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, primarily by cytochrome P450 3A4 (CYP3A4). Systemic clearance of solifenacin is approximately 9.5 L/hour, and its terminal half-life 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 is recovered in urine and 23% in feces. In urine, approximately 11% of the radioactive label is excreted as unchanged active substance; about 18% as N-oxide metabolite, 9% as 4R-hydroxy-N-oxide metabolite, and 8% as 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 mg 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 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 independent of patient gender.

Race. Race does not influence 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 half-life by over 60%. A statistically significant correlation has been 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 7–9), Cmax remains unchanged, AUC increases by 60%, and 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) micturition urges characteristic of patients with overactive bladder syndrome.

Contraindications.

• The medicinal product is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• in patients with urinary retention, severe gastrointestinal disorders (including toxic megacolon), myasthenia gravis, or closed-angle glaucoma, and in patients at risk of developing these conditions;
• during hemodialysis (see section "Pharmacological properties");
• in patients with severe hepatic impairment (see section "Pharmacological properties");
• 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.

When administered concomitantly with other medicinal products possessing anticholinergic properties, more pronounced therapeutic and adverse effects may occur. After discontinuation of Nihisem, approximately a one-week interval should be observed before initiating anticholinergic therapy with other medicinal products. 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 hepatic microsomal enzymes CYP1A1/2, 2C9, 2C19, 2D6, or 3A4. Therefore, it is unlikely that solifenacin affects the clearance of medicinal products metabolized by 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 CYP3A4 inhibitor, resulted in a doubling of solifenacin AUC, while administration of ketoconazole at a dose of 400 mg/day caused a threefold increase in solifenacin AUC. Therefore, the maximum dose of Nihisem should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent inhibitors of CYP3A4 enzyme (e.g., ritonavir, nelfinavir, itraconazole) (see section "Method of administration and dosage").

Concomitant use of solifenacin and a strong inhibitor of CYP3A4 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 substrates with high affinity for CYP3A4 and its metabolites on solifenacin exposure, has not been studied. Since solifenacin is metabolized by CYP3A4, pharmacokinetic interactions are possible with other substrates of this enzyme that have high affinity (e.g., verapamil, diltiazem), and with inducers of CYP3A4 enzyme (e.g., rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of other medicinal products.

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

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

Digoxin. Administration of the medicinal product does not affect the pharmacokinetics of digoxin.

Special precautions for use

Before initiating treatment with the medicinal product Nihisem, other potential causes of frequent urination should be ruled out (e.g. heart failure or kidney disease). If a urinary tract infection is diagnosed, appropriate antibacterial therapy should be initiated.

The medicinal product should be used with caution in patients:

• with clinically significant obstruction of the bladder outlet, 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 7–9) (see sections "Pharmacological properties" and "Dosage and administration"); doses in these patients should not exceed 5 mg;
• receiving concomitant strong CYP3A4 inhibitors, such as ketoconazole (see sections "Interaction with other medicinal products and other forms of interactions" and "Dosage and administration");
• with hiatal hernia and/or gastroesophageal reflux and/or those who are concurrently taking medicinal products (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

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

The safety and efficacy of the medicinal product have not been established in patients with increased activity of the neurogenic origin sphincter.

Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate. If angioedema occurs, treatment with solifenacin succinate should be discontinued and appropriate measures should be taken or appropriate therapy initiated.

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

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

The medicinal product contains lactose. This medicinal product should not be used in patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. There are no clinical data in women who became pregnant during treatment with solifenacin. Animal studies have not shown direct adverse effects on fertility, embryonic/fetal development, or parturition. 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 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 the medicinal product Nihisem is not recommended during breastfeeding.

Ability to influence the speed of reactions when driving or operating machinery.

Since solifenacin, like other anticholinergic drugs, may cause blurred vision and, less frequently, somnolence and increased fatigue (see section "Adverse reactions"), the use of this medicinal product may impair the ability to drive a vehicle or operate machinery.

Method of Administration and Dosage

Adults, including elderly patients

The recommended dose is 5 mg of the medicinal product 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). In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the drug should be used with caution at a dose not exceeding 5 mg once daily (see section "Pharmacological Properties").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child–Pugh score 7–9), the medicinal product should be administered with caution and the dose should not exceed 5 mg once daily (see section "Pharmacological Properties").

When using potent cytochrome P450 3A4 inhibitors

The maximum dose of the medicinal product should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other strong inhibitors of cytochrome CYP3A4 isoenzyme, such as ritonavir, nelfinavir, or itraconazole (see section "Interaction with other medicinal products and other forms of interaction").

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

Children

Safety and efficacy of the drug in children have not been established; therefore, Nigisem 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 includes:

• severe central nervous system anticholinergic effects such as hallucinations or increased agitation: treat with physostigmine or carbachol;
• seizures or increased agitation: treat with benzodiazepines;
• respiratory insufficiency: treat with artificial ventilation;
• tachycardia: treat with beta-blockers;
• urinary retention: treat with catheterization;
• mydriasis: treat with ophthalmic drops, e.g. pilocarpine, and/or place 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 prolong the QT interval) and patients with cardiac diseases (myocardial ischemia, arrhythmia, congestive heart failure).

Adverse reactions

The medicinal product Nihysem may cause adverse reactions related to the anticholinergic action of solifenacin, which are generally mild or moderate. The frequency of these reactions depends on the dose of the drug.

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

The table below lists other adverse reactions observed during clinical trials of Nihysem and in the post-marketing period.

*Post-registration period.

Reporting of adverse reactions.

Reporting of adverse reactions following registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua