Везикар®

General characteristics. Structure:

Active agent – a solifenatsina succinate of 5 mg, excipients – lactoses monohydrate, starch corn, a gipromelloza of 3 MPas • with, magnesium stearate, the water purified; structure of a film covering: опадрай yellow 03F12967 (a gipromelloza of 6 MPas • with, talc, a macrogoal 8000, titanium dioxide, ferrous oxide yellow). the tablet of 10 mg contains a odn: a kernel – active agent – a solifenatsina succinate of 10 mg, excipients – lactoses monohydrate, starch corn, a gipromelloza 3 мПас, magnesium stearate, the water purified; structure of a film covering: опадрай pink 03F14895 (a gipromelloza of 6 MPas • with, talc, a macrogoal 8000, titanium dioxide, ferrous oxide red).
Description
Tablet of 5 mg – a round, biconvex tablet, coated light yellow color, having marking "150" and a logo of the company on one party. a tabletka of 10 mg – a round, biconvex tablet, coated, light pink color, having marking "151" and a logo of the company on one party

Pharmacological properties:

Pharmacodynamics. The pharmacological researches conducted by in vitro and in vivo showed what солифенацин is a specific competitive inhibitor of muskarinovy receptors, preferential subtype M3. Also it was established what солифенацин has low or lack of affinity to various other receptors and ion channels. the drug effektivnost Vezikar in doses of 5 mg and 10 mg studied in several double blind people, randomized, controlled clinical tests on men and women with a syndrome of a hyperactive bladder was observed within the first week of treatment and stabilized for the next 12 weeks of treatment. The maximum effect of Vezikar can be revealed in 4 weeks. Efficiency remains during prolonged use (at least – 12 months).

Pharmacokinetics. General characteristics
Absorption: The maximum concentration in plasma (Cmax) is reached in 3-8 hours. Time of achievement of the maximum concentration (tmax) does not depend on a dose. Cmax and the area under a curve (AUC) of dependence of concentration from time increase in proportion to increase in a dose from 5 to 40 mg. Absolute bioavailability – 90%. Meal does not influence Cmax and PPK of a solifenatsin.
Distribution: The volume of distribution of a solifenatsin after intravenous administration makes about 600 l. Solifenatsin substantially (about 98%) is connected with plasma proteins, is preferential with α1-кислым a glycoprotein.
Metabolism: Solifenatsin is actively metabolized by a liver, preferential P450 ZA4 cytochrome (CYP3A4). However there are alternative metabolic paths by means of which metabolism of a solifenatsin can be carried out. The system clearance of a solifenatsin makes about 9,5 l/hour, and the final elimination half-life is equal to 45-68 hours. After administration of drug inside in plasma in addition to a solifenatsin the following metabolites were identified: one pharmacological active (4R-gidroksisolifenatsin) and three inactive (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of a solifenatsin).
Removal: After single introduction of 10 mg of a 14C-marked solifenatsin 26 days later about 70% of radioactivity were revealed in urine and 23% in excrements. In urine about 11% of radioactivity about 18% in the form of a N-oxidic metabolite, 9% in the form of a 4R-hydroxy-N-oxidic metabolite and 8% in the form of metabolite 4R-hydroxy (an active metabolite) are revealed in the form of not changed active agent.
The pharmacokinetics of a solifenatsin is linear in the therapeutic range of doses.
Features of pharmacokinetics at separate categories of patients
Age: There is no need to adjust a dose depending on age of patients. Researches showed that healthy elderly individuals (from 65 to 80 years) had a similar the exposure of a solifenatsin (5 and 10 mg) expressed as PPK and at healthy young individuals (<55 years). The average speed of absorption expressed as tmax. was slightly lower, and the final elimination half-life is about 20% longer at elderly people. These insignificant distinctions are not clinically significant. The pharmacokinetics of a solifenatsin was not defined at children and teenagers. Floor: The pharmacokinetics of a solifenatsin does not depend on a sex of the patient. Race: The race does not influence pharmacokinetics of a solifenatsin. Renal failure: PPK and Cmax of a solifenatsin at patients with a slight and moderate renal failure slightly differ from the corresponding indicators at healthy volunteers. At patients with a heavy renal failure (clearance of creatinine <30 ml/min.) exposure of a solifenatsin is much higher – increase in Cmax makes about 30%, PPK – more than 100% and t1/2-more than 60%. Statistically significant interrelation between clearance of creatinine and clearance of a solifenatsin is noted. The pharmacokinetics at the patients who are exposed to a hemodialysis was not studied.
Liver failure: At patients with a moderate liver failure (an indicator of Child-Pugh from 7 to 9) the size Cmax does not change, PPK increases by 60%, t1/2 increases twice. The pharmacokinetics at patients did not decide on a heavy liver failure.

Indications to use:

Treatment of an urgentny (imperative) incontience of urine, the speeded-up urination and urgentny (imperative) desires to an urination, characteristic of patients with a syndrome of a hyperactive bladder.

Route of administration and doses:

On 5 mg once a day inside, washing down with liquid, irrespective of meal time. If necessary the dose can be increased to 10 mg once a day.

Features of use:

Before beginning treatment by Vezikar, it is necessary to establish whether there are no other reasons of the speeded-up urination (heart failure or a disease of kidneys). If the infection of uric ways is revealed, it is necessary to begin the corresponding antibacterial treatment. Vezikar patients should appoint with care:
• with clinically significant obstruction of outlet opening of a bladder leading to risk of development of an ischuria;
• with gastrointestinal obstructive diseases;
• with risk of the lowered motility of digestive tract;
• with heavy renal (clearance of creatinine <30 ml a minute) and moderate hepatic (an indicator of Child-Pugh from 7 to 9) insufficiency; doses for these patients should not exceed 5 mg;
• at the same time accepting strong CYP3A4 inhibitor, for example, кетоконазол;
• with hernia of an esophageal opening of a diaphragm, a gastroezofagalny reflux and to the patients who are at the same time accepting medicines (for example, bisfosfonata) which can cause or strengthen an esophagitis;
• with autonomous neuropathy.
Patients with rare inherited disorders of portability of a galactose, a lactose intolerance of falls (Sami), glyukozo-galaktozny malabsorption should not accept drug.

Use at pregnancy and in the period of a lactation
There are no clinical data on women who became pregnant during reception of a solifenatsin. Researches on animals did not reveal a direct adverse effect on fertility, development of an embryo/fruit or childbirth. It is necessary to be careful at purpose of this drug to pregnant women. nt data on excretion of a solifenatsin with milk at people. Vezikar's use is not recommended during breastfeeding.

Influence on ability to drive the car and to manage mechanisms
Solifenatsin, like other anticholinergic drugs, can cause an illegibility of visual perception, and also (seldom) drowsiness and feeling of fatigue that can have an adverse effect on ability to drive the car and to work with mechanisms.

Side effects:

Vezikar can cause the side effects connected with anticholinergic action of a solifenatsin, is more often than weak or moderate expressiveness. Frequency of these undesirable effects depends on a dose. The most often noted side effect of Vezikar – dryness in a mouth. It was observed at 11% of the patients receiving a dose of 5 mg a day at 22% of the patients receiving a dose of 10 mg a day and at 4% receiving placebo. Expressiveness of dryness in a mouth usually was weak and only in rare instances led to treatment interruption. In general the commitment to treatment (комплаенс) was very high.

In the table other side effects registered in clinical trials of Vezikar are included below:

	Frequent (> 1/100, <1/10)	Infrequent (> 1/1000, <1/100)	Rare (> 1/10000, <1/1000)
Disturbances from outside digestive tract	lock, nausea, dyspepsia, abdominal pain	gastroezofagalny reflux disease, dryness of a throat	Colic impassability, coprostasis
Infections and invasions		infection of urinary tract
Disturbances from a nervous system		drowsiness, dysgeusia (taste disturbance)
Disturbances from organs of sight	sight illegibility (accommodation disturbance)	xerophthalmus
Disturbances of the general state		fatigue, hypostasis of the lower extremities
Disturbances from respiratory organs, a thorax and a mediastinum		dryness of a nasal cavity
Disturbances from skin and hypodermic cellulose		xeroderma
Disturbances from kidneys and urinary tract		difficulty of an urination	urination delay

Allergic reactions during clinical tests were not noted. However the possibility of allergic reactions should not be excluded.  

Interaction with other medicines:

Pharmacological interaction
The accompanying treatment by medicines with anticholinergic properties can result in more expressed therapeutic and undesirable effects. After the termination of reception of a solifenatsin it is necessary to take approximately week break before beginning treatment with other anticholinergic drug. The therapeutic effect can be reduced at a concomitant use of agonists of cholinergic receptors. Solifenatsin can reduce effect of the medicines stimulating motility of digestive tract, for example – Metoclopramidum and a tsizaprid.
Pharmacokinetic interaction
The researches in vitro showed what in therapeutic concentration солифенацин does not inhibit CYP1A 1/2, 2S9, 2S19, 2D6 or ZA4 allocated from microsomes of a liver of the person. Therefore it is improbable that солифенацин will change clearance of drugs, metaboliziruyemy these CYP enzymes.
Impact of other medicines on pharmacokinetics of a solifenatsin.
Solifenatsin is metabolized by CYP3A4. Simultaneous introduction of a ketokonazol (200 mg a day), strong CYP3A4 inhibitor, caused double increase in PPK of dependence of concentration from time of a solifenatsin, and in a dose of 400 mg/day – triple increase. Therefore the maximum dose of Vezikar should not exceed 5 mg if the patient at the same time accepts кетоконазол or therapeutic doses of other strong CYP3A4 inhibitors (such as ритонавир, нелфинавир. итраконазол). Simultaneous treatment solifenatsiny and strong CYP3A4 inhibitor is contraindicated to patients with a heavy renal failure or with a moderate liver failure. As солифенацин CYP3A4 is metabolized, pharmacokinetic interactions with other CYP3A4 substrates with higher affinity (verapamil, diltiazem) and with the inductors CYP3A4 (rifampicin, Phenytoinum, carbamazepine) are possible.
Influence of a solifenatsin on pharmacokinetics of other medicines
Oral contraceptives: Pharmacokinetic interaction of a solifenatsin and the combined oral contraceptives is not revealed (ethenylestradiollevonorgestrel).
Warfarin: Vezikar's reception did not cause changes of pharmacokinetics of R-warfarin or S-warfarin or their influence on a prothrombin time.
Digoxin: Vezikar's reception did not exert impact on digoxin pharmacokinetics.

Contraindications:

- urination delay;
- a serious gastrointestinal illness (including toxic megacolon);
- gravis myasthenia;
- closed-angle glaucoma;
- hypersensitivity to drug components;
- carrying out hemodialysis;
- heavy liver failure;
- a heavy renal failure or a moderate liver failure at simultaneous treatment by strong CYP3A4 inhibitors, for example, ketokonazoly.

Overdose:

The highest dose of a solifenatsin which was used by volunteers made 100 mg in the form of a single dose. At this dose the following side effects were most often noted: a headache (easy), dryness in a mouth (moderate), dizziness (moderate), drowsiness (easy) and an ambiguity of sight (moderate). About cases of acute overdoses it was not reported. In cases of overdose it is necessary to appoint absorbent carbon, to make a gastric lavage, but it is not necessary to cause vomiting.
As well as in cases of overdose of other anticholinergics, symptoms it is necessary to treat as follows:
• at heavy anticholinergic effects of the central action (a hallucination, the expressed excitability) – physostigmine or карбахол;
• at spasms or the expressed excitability – benzodiazepines;
• at respiratory insufficiency – an artificial respiration;
• at tachycardia – beta-blockers;
• at an urination delay – catheterization;
• at a mydriasis – to dig in Pilocarpinum in eyes and/or to place the patient in the dark room.
As well as in case of overdose of other anticholinergic drugs, special attention should be paid to patients with the established risk of lengthening of an interval of QT (i.e. at a hypopotassemia, bradycardia and at a concomitant use of the drugs causing lengthenings of an interval of QT) and to patients with heart diseases (ischemia of a myocardium, arrhythmia, congestive heart failure).

Storage conditions:

To store at a temperature not above 25 °C in the place, unavailable to children. Period of validity 3 years. 
Препарат it is not necessary to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister, on 1 or 3 blisters in a cardboard pack with the application instruction.