Solifenacin succinate

NIGISEM 5 mg film-coated tablets

 

Instruction manual

For medical use of the drug

Nigisem

(nigisem)

Structure:

Active ingredient: solifenacin succinate;

1 tablet contains solifenacin succinate 5 mg or 10 mg;

Excipients: lactose, monohydrate; corn starch; hypromellose (hydroxypropyl methyl cellulose); magnesium stearate;

5 mg tablet coating: opadry ii yellow film coating mixture: lactose, monohydrate; hypromellose (hydroxypropyl methyl cellulose); polyethylene glycol (macrogol); titanium dioxide (e 171); triacetin; iron oxide yellow (e 172);

10 mg tablet coating: opadry pink film coating mixture: talc; hypromellose (hydroxypropyl methyl cellulose); polyethylene glycol (macrogol); titanium dioxide (e 171); iron oxide red (e 172).

Dosage form.

Film-coated tablets.

Basic physical and chemical properties:

for tablets of 5 mg: tablets of a round shape with a biconvex surface, coated with a film membrane of light yellow color;

for tablets of 10 mg: round-shaped tablets with a biconvex surface, covered with a film of light pink color.

Pharmacotherapeutic group.

Means used in urology. agents for the treatment of frequent urination and urinary incontinence. code atx g04b d08.

Pharmacological properties.

Pharmacodynamics

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

In vitro and in vivo studies have shown that solifenacin is a competitive specific antagonist of cholinergic receptors predominantly M₃ subtype. It was also found that solifenacin has a weak affinity or lack of affinity with other receptors and test ion channels.

It is known that the effectiveness of the drug, which was studied in several double-blind, randomized, controlled clinical trials in men and women with overactive bladder syndrome, was observed already at the 1st week of treatment and stabilized over the next 12 weeks of treatment. In open studies with prolonged use, it has been shown that effectiveness is maintained for at least 12 months.

Pharmacokinetics

Absorption. After taking the tablets, the maximum concentration of solifenacin in the blood plasma (C_max) is reached in 3–8 hours. Time to reach maximum concentration (t_max) does not depend on the dose of the drug. Indicators C_max and the area under the curve (AUC) increases in proportion to the dose in the range of 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Eating on C value_max and AUC solifenacin is not affected.

Distribution. Solifenacin to a large extent (almost 98%) binds to plasma proteins, mainly with a₁-acid glycoprotein.

Metabolism. Solifenacin is largely metabolized in the liver, mainly by cytochrome P450 3A4 (CYP3A4). The systemic clearance of solifenacin is approximately 9.5 l / h, and the terminal half-life is 45–68 hours. After oral administration of the drug in blood plasma, in addition to solifenacin, 1 pharmacologically active (4R-hydroxysolifenacin) and 3 inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-solifenacin oxide) were identified.

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

Dose dependence. In the range of therapeutic doses, the pharmacokinetics of the drug is linear.

Features of pharmacokinetics in certain categories of patients.

Age. There is no need to adjust the dose depending on the age of the patients.Studies have shown that exposure to solifenacin (5 mg and 10 mg), expressed by AUC, was similar in healthy elderly volunteers (65 to 80 years old) and in healthy young and mature volunteers (max, was slightly lower and the end period elimination half-life is 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.

Floor. The pharmacokinetics of solifenacin is independent of the patient’s gender.

Race. Race does not affect the pharmacokinetics of solifenacin.

Renal failure. AUC and C_max solifenacin in patients with mild to moderate renal failure slightly differ from those in healthy volunteers. In patients with severe renal failure (creatinine clearance ≤ 30 ml / min), exposure to solifenacin is significantly higher: an increase in C_max is approximately 30%, AUC is more than 100% and the half-life is more than 60%. There was a statistically significant relationship between creatinine clearance and solifenacin clearance. The pharmacokinetics of patients who underwent hemodialysis were not studied.

Liver failure. In patients with moderate liver failure (Child-Pugh score 7–9), the value of C_max does not change, AUC increases by 60% and the half-life is doubled. The pharmacokinetics in patients with severe renal failure have not been studied.

Clinical characteristics.

Indications.

Symptomatic treatment of urgent (imperative) urinary incontinence and / or frequent urination, as well as urgent (imperative) urination, 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;

• patients with urinary retention, with severe gastrointestinal diseases (including toxic megacolon), with myasthenia gravis or with angle-closure glaucoma, and patients at risk of developing these conditions;
• during hemodialysis (see section "Pharmacokinetics");
• patients with severe liver failure (see section "Pharmacokinetics");
• patients with severe renal failure or moderate liver failure who are being treated with potent CYP3A4 inhibitors, such as ketoconazole (see section “Interaction with other drugs and other types of interactions”).

Interaction with other drugs and other types of interactions.

Pharmacological interactions.

The simultaneous use of other drugs with anticholinergic properties can have more pronounced therapeutic effects, as well as adverse reactions. After stopping the use of the drug Nigisem before taking the following medications of anticholinergic therapy, it is necessary to maintain an approximately one-week interval. The therapeutic effect of solifenacin may decrease with the concomitant use of cholinergic receptor agonists. Solifenacin can reduce the effect of drugs 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 microsomes CYP1A1 / 2, 2C9, 2C19, 2D6 or 3A4. Thus, solifenacin is unlikely to affect the clearance of drugs that are metabolized by CYP enzymes.

The effect of other drugs on the pharmacokinetics of solifenacin.

Solifenacin is metabolized by the enzyme CYP3A4.The simultaneous use of ketoconazole (200 mg / day), a potent inhibitor of CYP3A4, led to a twofold increase in the AUC of solifenacin, while taking ketoconazole at a dose of 400 mg / day increases the AUC of solifenacin by 3 times. Thus, the maximum dose of Nigisem should be limited to 5 mg while using other active inhibitors of the CYP3A4 enzyme (for example, ritonavir, nelfinavir, itraconazole) with ketoconazole or therapeutic doses (see section "Dosage and Administration").

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

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

The effect of solifenacin on the pharmacokinetics of drugs.

Oral contraceptives. Taking the drug does not affect the pharmacokinetic interaction of solifenacin with combined oral contraceptives (ethinyl estradiol / levonorgestrel).

Warfarin. Taking 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.

Features of the application.

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 urinary tract infection is detected, appropriate antibiotic therapy should be initiated.

The drug should be taken with caution in patients:

• with clinically significant obstruction of the outlet of the bladder, which leads to the risk of urinary retention;
• with gastrointestinal obstructive diseases;
• with a risk of decreased motility of the gastrointestinal tract;
• with severe renal (creatinine clearance ≤ 30 ml / min) and moderate hepatic (Child-Pugh score 7–9) insufficiency (see sections “Dosage and administration” and “Pharmaco-kinetics”); doses for these patients should not exceed 5 mg;
• while taking strong CYP3A4 inhibitors, such as ketoconazole (see sections "Dosage and administration" and "Interaction with other drugs and other types of interactions");
• with a hiatal hernia and / or gastroesophageal reflux and / or those who are simultaneously taking medications (such as bisphosphonates) that may cause or enhance esophagitis;
• autonomic neuropathy.

Patients with risk factors such as the previously reported QT interval lengthening syndrome and hypokalemia experienced QT interval lengthening and ventricular flutter / flicker (torsade de pointes).

The safety and effectiveness of the use of the drug in patients with increased activity of a sphincter of neurogenic origin have not been investigated.

In some patients taking solifenacin succinate, angioedema with airway obstruction has been reported. If Quincke edema occurs, treatment of solifenacin with succinate should be discontinued and appropriate measures should be taken or necessary treatment should be prescribed.

Anaphylactic reactions have been observed in some patients taking solifenacin succinate.If anaphylactic reactions occur, treatment of solifenacin with succinate should be discontinued and appropriate measures taken or the necessary treatment prescribed.

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

The composition of the drug includes lactose. This drug should not be taken in patients with rare hereditary diseases associated with galactose intolerance, Lapp lactase deficiency or impaired glucose-galactose malabsorption.

Use during pregnancy or lactation.

Pregnancy. There are no clinical data on women who became pregnant during the use of solifenacin. animal studies did not reveal a direct adverse effect on fertility, development of the embryo / fetus or childbirth. potential risk is unknown. caution should be exercised when using this drug for pregnant women.

Breastfeeding. There is no data on the excretion of solifenacin into breast milk. In mice, solifenacin and / or its metabolites penetrate into milk and cause dose-dependent growth failure in newborn mice. The use of the drug Nigisem is not recommended during lactation.

The ability to influence the reaction rate when driving vehicles or other mechanisms.

Due to the fact that solifenacin, like other anticholinergics, can cause blurred vision and rarely drowsiness and increased fatigue (see section “adverse reactions”), taking the drug can negatively affect the ability to drive a car and work with other mechanisms.

Dosage and administration.

Adults, including elderly patients.

The recommended dose is 5 mg of the drug 1 time per day. If necessary, the dose can be increased to 10 mg once a day.

Patients with renal failure.

No dose adjustment is required for patients with moderate to moderate renal failure (creatinine clearance 30 ml / min). Patients with severe renal failure (creatinine clearance ≤ 30 ml / min) should be used with caution in a dose of not more than 5 mg once a day.

Patients with liver failure.

Dose adjustment is not required for patients with moderate liver failure. Patients with moderate liver failure (Child-Pugh score 7–9) should take the drug with caution and not exceed the dosage of 5 mg once a day.

The use of potent inhibitors of cytochrome P450 3A4.

The maximum dose of the drug should be limited to 5 mg while taking with ketoconazole or therapeutic doses of other active inhibitors of the CYP3A4 enzyme, such as ritonavir, nelfinavir, itraconazole (see section “Interaction with other drugs and other types of interactions”).

Take the medicine orally, swallow the tablets whole with a liquid, regardless of the meal.

Children.

The safety and efficacy of the drug for children have not been investigated; the drug nigisem should not be prescribed in this category of patients.

Overdose.

Symptoms an overdose of solifenacin succinate can lead to severe anticholinergic effects. the highest dose of solifenacin succinate, taken accidentally by one patient, was 280 mg for 5 hours, as a result of which changes in the mental state were observed, but did not require hospitalization.

Treatment. In case of an overdose of solifenacin succinate, the patient must take activated charcoal. Gastric lavage may be helpful if done within 1 hour after an overdose, but vomiting should not be induced.

For other anticholinergic effects, symptoms should be treated as follows:

- severe anticholinergic effects from the central nervous system, such as hallucinations or increased irritability - use physostigmine or carbachol;

• convulsions or increased excitability - benzodiazepines are administered;
• insufficiency of the respiratory system - carry out artificial ventilation of the lungs;
• tachycardia - beta blockers are used;
• urinary retention - carry out catheterization;
• mydriasis - apply eye drops, for example pilocarpine, and / or put the patient in a dark room.

As in the case of an overdose of other anticholinergics, special attention should be given to patients with an established risk of lengthening the QT interval (with hypokalemia, bradycardia, while the use of drugs that cause prolongation of the QT interval) and patients with heart diseases (myocardial ischemia, arrhythmias, congestive heart failure )

Adverse Reactions

Infections and infestations: urinary tract infections, cystitis;

from the immune system: anaphylactic reaction;

from the side of metabolism and digestion: decreased appetite, hyperkalemia;

from the psyche: hallucinations, confusion, delirium;

from the nervous system: drowsiness, taste disturbance, dizziness, headache;

on the part of the organs of vision: blurred vision, dry eyes, glaucoma;

on the part of the heart: palpitations / flickering of the ventricles (torsade de pointes), lengthening of the QT interval on the electrocardiogram, atrial fibrillation, palpitations, tachycardia;

from the respiratory system, chest and mediastinal organs: dry nasal mucosa, dysphonia;

from the gastrointestinal tract: dry mouth, constipation, nausea, dyspepsia, abdominal pain, gastroesophageal reflux, dry throat, obstruction of the large intestine, coprostasis, vomiting, intestinal obstruction, abdominal discomfort;

hepatobiliary disorders: impaired liver function, violations in the data of laboratory studies of liver samples;

on the part of the skin and subcutaneous tissues: dry skin, itching, rash, erythema multiforme, urticaria, Quinckes edema, exfoliative dermatitis;

from the musculoskeletal system and connective tissue: muscle weakness;

from the kidneys and urinary system: difficulty urinating, urinary retention, renal failure;

general disorders: fatigue, peripheral edema.

Shelf life.

2 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a pack.

Vacation category.

On prescription.

Manufacturer.

AO Kiev Vitamin Plant.

The location of the manufacturer and the address of the place of business.

04073, Ukraine, Kiev, st. Kopylovskaya, 38.

Website: www.vitamin.com.ua