Vesicar, 5 mg 30 pcs.

Pharmacodynamics

In vitro and in vivo pharmacological studies have shown that solifenacin is a specific competitive inhibitor of muscarinic receptors, predominantly of the M3 subtype. Solifenacin was also found to have low affinity or no interaction with other receptors and ion channels.

The efficacy of Vesicar, studied in several double-blind, randomized controlled clinical trials in men and women with overactive bladder syndrome, was observed during the first week of treatment and stabilized during the following 12 weeks of treatment. The maximal effect of Vesicar can be detected after 4 weeks. The efficacy lasts for long-term use (at least 12 months).

Pharmacokinetics

General characteristics

Absorption. Cmax is reached after 3-8 h. The time to reach Cmax is independent of the dose. Cmax and AUC increase in proportion to dose increase from 5 to 40 mg. Absolute bioavailability is 90%. Food intake has no effect on Cmax and AUC of solifenacin.

Distribution. The volume of distribution of solifenacin after intravenous administration is 600 l. Solifenacin is largely (about 98%) bound to plasma proteins, mainly to α1-acid glycoprotein.

Metabolism. Solifenacin is actively metabolized by the liver, mainly by cytochrome P450 3A4 (CYP3A4). However, there are alternative metabolic pathways by which solifenacin may be metabolized. The systemic Cl of solifenacin is about 9.5 l/h, and the final T1/2 is 45-68 h. After oral administration the following metabolites were identified in plasma in addition to solifenacin: one pharmacologically active (4R-hydroxysolifenacin) and three inactive (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide solifenacin).

Elimination. 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 the urine, approximately 11% of radioactivity was found as unchanged active ingredient, about 18% as N-oxide metabolite, 9% as 4R-hydroxy-N-oxide metabolite, and 8% as 4R-hydroxy metabolite (active metabolite).

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

Peculiarities of pharmacokinetics in certain categories of patients

Age. There is no need to adjust the dose according to the age of patients. Studies have shown that the exposure of solifenacin (5 and 10 mg), expressed as AUC, was similar in healthy elderly individuals (65 to 80 years) and healthy young individuals (max, was slightly lower, and the final T1/2 was approximately 20% longer in the elderly. These minor differences are not clinically significant.

The pharmacokinetics of solifenacin have not been determined in children and adolescents.

Pol. The pharmacokinetics of solifenacin are independent of the gender of the patient.

Race. Race has no effect on the pharmacokinetics of solifenacin.

Renal insufficiency. AUC and Cmax of solifenacin in patients with mild to moderate renal impairment are not significantly different from those in healthy volunteers. In patients with severe renal insufficiency (creatinine Cl ≤30 ml/min) solifenacin exposure is significantly higher (increase in Cmax is about 30%, AUC – >100% and T1/2 – more than 60%). There is a statistically significant relationship between creatinine clearance and solifenacin clearance. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Hepatic failure. In patients with moderate hepatic insufficiency (Child-Pugh index from 7 to 9) Cmax value is not changed, AUC is increased by 60%, T1/2 is doubled. Pharmacokinetics in patients with severe hepatic impairment was not determined.

Indications

Urgent (imperative) urinary incontinence, rapid urination and urgent (imperative) urge to urinate, characteristic of patients with overactive bladder syndrome.

Active ingredient

Composition

1 film-coated tablet contains
active ingredient:

solifenacin succinate 5 mg;

excipients:

Lactose monohydrate;

Corn starch;

Hypromellose 3 mPa-s;

Magnesium stearate;

Purified water

How to take, the dosage

Orally with liquid, regardless of the time of meals, 5 mg once a day.

If necessary, the dose may be increased to 10 mg once daily.

Interaction

Pharmacological interactions

Continuous treatment with drugs with anticholinergic properties may lead to more pronounced therapeutic and adverse effects. After stopping solifenacin, a break of approximately one week should be taken before starting treatment with another anticholinergic drug. The therapeutic effect may be reduced by concomitant administration of cholinergic receptor agonists. Solifenacin may decrease the effect of drugs that stimulate gastrointestinal motility, such as metoclopramide and cisapride.

Pharmacokinetic interaction

In vitro studies have shown that solifenacin does not inhibit CYP1A1/2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 isolated from human liver microsomes at therapeutic concentrations. Therefore, it is unlikely that solifenacin will alter the clearance of drugs metabolized by these CYP enzymes.

The effect of other drugs on the pharmacokinetics of solifenacin

Solifenacin is metabolized by CYP3A4. Concomitant administration of ketoconazole (200 mg daily), a strong CYP3A4 inhibitor, caused a twofold increase in AUC of solifenacin, and a threefold increase at a dose of 400 mg daily. Therefore, the maximum dose of Vezicar should not exceed 5 mg if the patient simultaneously takes ketoconazole or therapeutic doses of other strong CYP3A4 inhibitors (such as ritonavir, nelfinavir, itraconazole). Concomitant treatment with solifenacin and a strong 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.

The effect of solifenacin on the pharmacokinetics of other drugs

Internal contraceptives: no pharmacokinetic interaction of solifenacin and combined oral contraceptives (ethinylestradiol/levonorgestrel) was found.

Warfarin: Vesicar administration did not cause changes in the pharmacokinetics of R-warfarin or S-warfarin or their effect on PV.

Digoxin: Vesicar administration had no effect on the pharmacokinetics of digoxin.

Special Instructions

Before starting treatment with Vesicar, it should be determined whether there are no other causes of frequent urination (heart failure or kidney disease). If a urinary tract infection is detected, appropriate antibacterial treatment should be started. Vesicar should be prescribed with caution in patients:

– with clinically significant bladder outlet obstruction leading to risk of urinary retention;

– with gastrointestinal obstructive disease;

– with risk of decreased GI motility;

– with severe renal (creatinine Cl ≤30 mL/min) and moderate hepatic (Child-Pugh score of 7 to 9) insufficiency; doses for these patients should not exceed 5 mg;

– concomitantly taking a strong CYP3A4 inhibitor, such as ketoconazole;

– patients with esophageal hernia, gastroesophageal reflux, and patients taking concomitant medications (such as bisphosphonates) that may cause or aggravate esophagitis;

– with autonomic neuropathy.

Patients with rare hereditary galactose intolerance disorders, lactase deficiency lopari (Sami), glucose-galactose malabsorption should not take the drug.

Soliphenacin, like other anticholinergic drugs, may cause blurred vision and (rarely) drowsiness and fatigue, which may adversely affect the ability to drive and operate machinery.

Contraindications

Side effects

Vesicar may cause side effects associated with the anticholinergic effect of solifenacin, often of mild to moderate severity. The frequency of these adverse effects depends on the dose. The most frequently reported side effect of Vezicar is dry mouth. It was observed in 11% of patients receiving a dose of 5 mg daily, in 22% of patients receiving a dose of 10 mg daily, and in 4% receiving a placebo. The severity of dry mouth was usually mild and only rarely resulted in treatment interruption. Overall, adherence to treatment (compliance) was very high.

The table below summarizes the remaining side effects reported in the Vezicar clinical trials:

Side effectsFrequently
(≥1/100,Infrequently
(≥1/1000,Rarely
(≥1/10000,Gastrointestinal disorders constipation, nausea, dyspepsia, abdominal paingastroesophageal reflux disease, dry pharyngeal obstruction, coprostasisInfections and invasions urinary tract infection Nervous system disorders sleepiness, dysgeusia (taste disorder) Visual disorders fuzzy vision (accommodation disorders)dry eyes General condition disorders fatigue Lower limb swelling Respiratory, chest and mediastinum disorders Nasal dryness Skin and subcutaneous tissue disorders Skin dryness Kidney and urinary tract disorders Difficulty in urination Delayed urination/p>

Allergic reactions during clinical trials were not observed. However, the possibility of allergic reactions should not be excluded.

Overdose

The highest dose of solifenacin used by volunteers was 100 mg as a single dose. The most commonly reported side effects at this dose were headache (mild), dry mouth (moderate), dizziness (moderate), drowsiness (mild), and blurred vision (moderate). No cases of acute overdose have been reported.

Treatment: administration of activated charcoal, gastric lavage; vomiting should not be induced.

As in cases of overdose of other anticholinergic agents, symptoms should be treated as follows:

For severe central anticholinergic effects (hallucinations, marked excitability), physostigmine or carbachol;

For seizures or marked excitability, benzodiazepines;

– for respiratory failure – artificial respiration;

– for tachycardia – beta-adrenoblockers;

– for urinary retention – catheterization;

– for mydriasis – eye drops pilocarpine and/or darken the room where the patient is.

As with overdose of other anticholinergic drugs, special attention should be paid to patients with an established risk of QT interval prolongation (i.e., hypokalemia, bradycardia and concomitant administration of QT interval prolongers) and patients with cardiac disease (myocardial ischemia, arrhythmia, congestive heart failure).

Pregnancy use

There are no clinical data on women who have become pregnant while taking solifenacin.

Animal studies have shown no direct adverse effects on fertility, embryo/fetal development or childbirth.

Caution should be exercised when prescribing this drug in pregnant women.

There are no data on the excretion of solifenacin with milk in humans.

The use of Vezicar is not recommended during breastfeeding.

Similarities