Instructions Nigisem film-coated tablets 5 mg blister No. 30
Composition
active ingredient: solifenacin succinate;
1 tablet contains solifenacin succinate 5 mg;
excipients: lactose monohydrate; corn starch; hypromellose (hydroxypropylmethylcellulose); magnesium stearate;
shell 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).
Dosage form
Film-coated tablets.
Main physicochemical properties:
for 5 mg tablets: round tablets with a biconvex surface, coated with a light yellow film coating.
Pharmacotherapeutic group
Drugs used in urology. Drugs for the treatment of frequent urination and urinary incontinence. ATX code G04B D08.
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, which are predominantly of the M3 subtype.
In vitro and in vivo studies have shown that solifenacin is a competitive, specific antagonist of cholinergic receptors, predominantly of the M3 subtype. Solifenacin has also been shown to have little or no affinity for other receptors and ion channels tested.
It is known that the efficacy of the drug, which was studied in several double-blind randomized controlled clinical trials in men and women with overactive bladder syndrome, was observed as early as the 1st week of treatment and stabilized over the next 12 weeks of treatment. In open-label studies with long-term use, efficacy has been shown to be maintained for at least 12 months.
Pharmacokinetics
Absorption. After taking the tablets, the maximum concentration of solifenacin in the blood plasma (Cmax) is reached after 3-8 hours. The time to reach the maximum concentration (tmax) does not depend on the dose of the drug. Cmax and area under the curve (AUC) increase proportionally to the dose in the range from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect the Cmax and AUC of solifenacin.
Distribution: Solifenacin is extensively (almost 98%) bound to plasma proteins, primarily α1-acid glycoprotein.
Metabolism: Solifenacin is extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). The systemic clearance of solifenacin is approximately 9.5 l/h and its terminal half-life is 45–68 hours. After oral administration, 1 pharmacologically active (4R-hydroxysolifenacin) and 3 inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been identified in plasma in addition to solifenacin.
Excretion: After a single dose of 10 mg of 14C-labeled solifenacin, approximately 70% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 11% of the radioactivity is excreted in the urine as unchanged active substance; approximately 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxymetabolite (active metabolite).
Dose dependence. In the therapeutic dose range, the pharmacokinetics of the drug are linear.
Features of pharmacokinetics in certain categories of patients
Age. No dose adjustment is necessary based on age. Studies have shown that exposure to solifenacin (5 mg and 10 mg), as expressed by AUC, was similar in healthy elderly volunteers (65 to 80 years) and healthy young and middle-aged volunteers (< 55 years). The mean rate of absorption, as expressed by tmax, was slightly slower and the terminal half-life was approximately 20% longer in elderly patients. These small differences are not clinically relevant.
The pharmacokinetics of solifenacin have not been studied in children and adolescents.
Gender: The pharmacokinetics of solifenacin are independent of the patient's gender.
Race: Race does not affect the pharmacokinetics of solifenacin.
Renal impairment. AUC and Cmax of solifenacin in patients with mild and moderate renal impairment are not significantly different from those in healthy volunteers. In patients with severe renal impairment (creatinine clearance < 30 ml/min), solifenacin exposure is significantly higher: Cmax increases of approximately 30%, AUC increases of more than 100% and half-life increases of more than 60%. A statistically significant relationship between creatinine clearance and solifenacin clearance was observed. Pharmacokinetics in patients undergoing haemodialysis have not been studied.
Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh score 7-9), Cmax is unchanged, AUC is increased by 60%, and half-life is doubled. Pharmacokinetics in patients with severe renal impairment have not been studied.
Indication
Symptomatic treatment of urge incontinence and/or frequent urination, as well as the urge to urinate, typical of patients with overactive bladder syndrome.
Contraindication
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 diseases (including toxic megacolon), myasthenia gravis or angle-closure glaucoma and patients at risk of developing these conditions; in patients undergoing hemodialysis (see section "Pharmacokinetics"); in patients with severe hepatic insufficiency (see section "Pharmacokinetics");
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 types of interactions").
Interaction with other medicinal products and other types of interactions
Pharmacological interactions
Concomitant administration of other drugs with anticholinergic properties may have more pronounced therapeutic effects, as well as undesirable effects. After discontinuation of Nigisem, an interval of approximately one week should be observed before taking the next anticholinergic therapy drugs. The therapeutic effect of solifenacin may be reduced with concomitant use of cholinergic receptor agonists. Solifenacin may reduce the effect of drugs that stimulate gastrointestinal peristalsis, such as metoclopramide and cisapride.
Pharmacokinetic interactions
In vitro studies have shown that solifenacin does not inhibit hepatic microsomal CYP1A1/2, 2C9, 2C19, 2D6 or 3A4 at therapeutic concentrations. Therefore, it is unlikely that solifenacin will affect the clearance of drugs metabolized by CYP enzymes.
Effect of other medicinal products on the pharmacokinetics of solifenacin
Solifenacin is metabolized by CYP3A4. Concomitant administration of ketoconazole (200 mg/day), a strong CYP3A4 inhibitor, resulted in a two-fold increase in solifenacin AUC, while ketoconazole 400 mg/day increased solifenacin AUC by a factor of 3. Therefore, the maximum dose of Nigisem should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors (e.g. ritonavir, nelfinavir, itraconazole) (see section 4.2).
Concomitant use of solifenacin and a strong CYP3A4 inhibitor is contraindicated in patients with severe renal 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 high-affinity substrates of this enzyme (e.g. verapamil, diltiazem) and inducers of the CYP3A4 enzyme (e.g. rifampicin, phenytoin, carbamazepine).
Effect of solifenacin on the pharmacokinetics of drugs
Oral contraceptives: The pharmacokinetic interaction of solifenacin with combined oral contraceptives (ethinyl estradiol/levonorgestrel) is not affected by co-administration.
Warfarin: The drug does not affect the pharmacokinetic interaction of R-warfarin or S-warfarin or their effect on prothrombin time.
Digoxin. Taking the drug does not affect the pharmacokinetics of digoxin.
Application features
Before starting treatment with the drug, it is necessary to establish the likelihood of other causes of frequent urination (heart failure or kidney disease). If a urinary tract infection is detected, appropriate antibacterial therapy should be initiated.
The medicine should be taken with caution in patients:
with clinically significant bladder outlet obstruction leading to a risk of urinary retention; with gastrointestinal obstructive diseases; with a risk of reduced gastrointestinal motility;
with severe renal (creatinine clearance < 30 ml/min) and moderate hepatic (Child-Pugh score 7-9) insufficiency (see sections "Dosage and administration" and "Pharmacokinetics"); doses for these patients should not exceed 5 mg;
with simultaneous use of strong CYP3A4 inhibitors, such as ketoconazole (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”);
with hiatal hernia and/or gastroesophageal reflux and/or those taking concomitant medications (such as bisphosphonates) that may cause or exacerbate esophagitis; with autonomic neuropathy.
QT prolongation and ventricular flutter/fibrillation (torsade de pointes) have been observed in patients with risk factors such as pre-existing long QT syndrome and hypokalemia.
Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate. If angioedema occurs, solifenacin succinate should be discontinued and appropriate measures or treatment instituted.
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 or treatment should be initiated.
The maximum effect of the drug is achieved no earlier than after 4 weeks of therapy.
This medicinal product contains lactose. This medicinal product should not be taken by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Ability to influence reaction speed when driving vehicles or other mechanisms
Since solifenacin, like other anticholinergic drugs, can cause blurred vision and, infrequently, drowsiness and fatigue (see section "Adverse reactions"), taking the drug may adversely affect the ability to drive and use machines.
Use during pregnancy or breastfeeding
Pregnancy. There are no clinical data on women who became pregnant while taking solifenacin. Animal studies do not indicate direct adverse effects on fertility, embryonal/fetal development or parturition. The potential risk is unknown. Caution should be exercised when using this drug in pregnant women.
Breastfeeding. There are no data on the excretion of solifenacin in breast milk. In mice, solifenacin and/or its metabolites pass into milk and cause dose-dependent growth failure in newborn mice. The use of Nigisem is not recommended during breastfeeding.
Method of administration and doses
Adults, including elderly patients.
The recommended dose is 5 mg of the drug once a day. If necessary, the dose can be increased to 10 mg once a day.
Patients with renal insufficiency
No dose adjustment is required 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 administered with caution at a dose not exceeding 5 mg once daily.
Patients with hepatic impairment: No dose adjustment is required for patients with moderate hepatic impairment. Patients with moderate hepatic impairment (Child-Pugh score 7–9) should take the drug with caution and not exceed a dosage of 5 mg once daily.
Use of potent cytochrome P450 3A4 inhibitors
The maximum dose of the drug should be limited to 5 mg when taken simultaneously with ketoconazole or therapeutic doses of other active inhibitors of the CYP3A4 enzyme, such as ritonavir, nelfinavir, itraconazole (see section "Interaction with other medicinal products and other types of interactions").
The medicine should be taken orally, swallowing the tablets whole with liquid, regardless of meals.
Children
The safety and efficacy of the drug in children have not been studied; Nigisem should not be prescribed to this category of patients.
Overdose
Symptoms: Overdose of solifenacin succinate may result in severe anticholinergic effects. The highest dose of solifenacin succinate accidentally taken by one patient was 280 mg over 5 hours, resulting in mental status changes that did not require hospitalization.
Treatment: In case of overdose with solifenacin succinate, the patient should be given activated charcoal. Gastric lavage may be useful if performed within 1 hour of overdose, but vomiting should not be induced.
Regarding other anticholinergic effects, symptoms should be treated as follows:
Severe anticholinergic effects on the central nervous system, such as hallucinations or hyperexcitability - use physostigmine or carbachol; Convulsions or hyperexcitability - use benzodiazepines; Respiratory failure - use artificial ventilation; Tachycardia - use a beta-blocker; Urinary retention - use catheterization; Mydriasis - use eye drops, such as pilocarpine, and/or place the patient in a dark room.
As with overdose with other anticholinergics, special attention should be paid to patients with an established risk of QT prolongation (hypokalemia, bradycardia, concomitant use of drugs that prolong the QT interval) and patients with cardiac disease (myocardial ischemia, arrhythmias, congestive heart failure).
Adverse reactions
Infections and infestations: urinary tract infections, cystitis;
from the immune system: anaphylactic reaction;
Metabolism and digestion: decreased appetite, hyperkalemia;
Mental: hallucinations, confusion, delusions;
on the part of the organs of vision: blurred vision, dry eyes, glaucoma;
Cardiac: ventricular flutter/fibrillation (torsade de pointes), prolongation of the QT interval on the electrocardiogram, atrial fibrillation, palpitations, tachycardia;
from the respiratory system, chest organs and mediastinum: dryness of the nasal mucosa, dysphonia;
Gastrointestinal: dry mouth, constipation, nausea, dyspepsia, abdominal pain, gastroesophageal reflux, dry throat, large intestine obstruction, coprostasis, vomiting, intestinal obstruction, abdominal discomfort;
hepatobiliary disorders: liver function disorders, abnormalities in laboratory data of liver tests;
Skin and subcutaneous tissue disorders: dry skin, itching, rash, erythema multiforme, urticaria, angioedema, exfoliative dermatitis;
Musculoskeletal and connective tissue disorders: muscle weakness;
from the kidneys and urinary system: difficulty urinating, urinary retention, renal failure;
general disorders: increased fatigue, peripheral edema.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and its business address
04073, Ukraine, Kyiv, Kopylivska St., 38.
