Vesicar® (Vesicare®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceSolifenacinSolifenacin
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  • Vesicar®
    pills inwards 
    Astellas Farma Europe BV     Netherlands
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    Each 5 mg tablet contains:

    composition of the core of the tablet: solifenacin succinate 5.0 mg, lactose monohydrate 107.5 mg, corn starch 30.0 mg, hypromellose 3 mPa s 6.0 mg, magnesium stearate 1.5 mg, purified water 54.0 mg ;

    film coating composition of the tablet: yellow opal yellow 03F12967 - 4.0 mg (hypromellose 6 mPa with - 61.83%, talc - 18.54%, macrogol 8000 - 11.6%, titanium dioxide - 7.88%, iron oxide yellow - 0.15%), purified water * - 36.0 mg.

    Each 10 mg tablet contains:

    tablet core composition: solifenacin succinate - 10,0 mg, lactose monohydrate - 102.5 mg, corn starch - 30.0 mg, hypromellose 3 mPa c - 6.0 mg, magnesium stearate - 1.5 mg, purified water * - 54.0 mg;

    composition of the film coating of the tablet: opadrai pink 03F14895 - 4.0 mg (hypromellose 6 mPa with - 62,0%, talc - 18,59%, macrogol 8000 - 11,63%, titanium dioxide - 7,75%, iron oxide red - 0,03%), purified water * - 36,0 mg.

    * - water is removed during production.

    Description:

    Vesicar® 5 mg

    Round, biconvex tablets, covered with a film coating of light yellow color, marked "150" and the company logo on one side.

    Vesicar® 10 mg

    Round, biconvex tablets covered with a film shell, light pink, marked "151" and the company logo on one side.

    Pharmacotherapeutic group:Spasmolytic agent
    ATX: & nbsp

    G.04.B.D   Spasmolytics

    G.04.B.D.08   Solifenacin

    Pharmacodynamics:

    Mechanism of action

    Solifenacin is a specific competitive antagonist of muscarinic receptors. The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine affects muscarinic receptors (mainly M3) and causes a reduction in detrusor. Pharmacological studies conducted in vitro and in vivo, showed that solifenacin is a specific competitive inhibitor of muscarinic receptors of the subtype M3. It was also found that solifenacin has a low or no affinity for various other receptors and ion channels.

    Pharmacodynamics

    The efficacy of Vesicar® in doses of 5 mg and 10 mg, studied in several double-blind, randomized, controlled clinical trials in men and women with hyperactive bladder syndrome, was observed during the first week of treatment and stabilized over the next 12 weeks of treatment. A long-term open clinical trial showed that efficacy persists for at least 12 months.After 12 weeks, approximately 50% of patients who suffered from urinary incontinence before treatment ceased to experience urinary incontinence, and 35% of patients achieved a decrease in urinary frequency of less than 8 per day. Treatment of symptoms of a hyperactive bladder (GMF) led to significant improvements in quality of life indicators. The maximum effect of Vesicare® can be detected after 4 weeks.

    Pharmacokinetics:

    General characteristics

    Absorption: The maximum concentration in plasma (CmOh) is achieved in 3-8 hours. Time to reach the maximum concentration (tmax) does not depend on the dose. FROMmOh and the area under the curve (AUC), the concentration dependences on time increase in proportion to the increase in the dose from 5 to 40 mg. Absolute bioavailability is 90%. Eating does not affect CmOh and AUC solifenacin.

    Distribution: The volume of solifenacin distribution after intravenous administration is approximately 600 liters. Solifenacin to a large extent (about 98%) is associated with plasma proteins, predominantly with α1acid glycoprotein.

    Metabolism: Solifenacin actively metabolized by the liver, predominantly isoenzyme CYP3A4.However, there are alternative metabolic pathways through which solifenacin metabolism can be realized. The systemic clearance of solifenacin is about 9.5 l / h, and the final half-life is 45-68 hours. After taking the drug inside the plasma, in addition to solifenacin, the following metabolites were identified: one pharmacologically active (4R-hydroxoliphenacin) and three inactive (N-glucuronide, N-oxide and 4R-hydroxy-Nsolifenacin oxide).

    Excretion: After a single administration of 10 mg 14C-labeled solifenacin 26 days later, about 70% of the radioactivity was detected in urine and 23% in feces. In urine, about 11% of the radioactivity was detected as an unchanged active substance, about 18% in the form Noxide metabolite, 9% as a 4R-hydroxy-N-oxide metabolite and 8% in the form 4R-hydroxy metabolite (active metabolite).

    The pharmacokinetics of solifenacin is linear in the therapeutic dose range.

    Peculiarities 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 the exposure of solifenacin (5 and 10 mg), expressed as AUC, was similar in healthy elderly individuals (65 to 80 years) and in healthy young individuals (<55 years).The average absorption rate, expressed as tmax, was somewhat lower, and the final half-life is approximately 20% longer in the elderly. These minor differences are not clinically significant.

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

    Floor: The pharmacokinetics of solifenacin does not depend on the patient's sex.

    Race: Race does not affect the pharmacokinetics of solifenacin.

    Renal insufficiency: AUC and CmOh solifenacin in patients with mild and moderate renal insufficiency are slightly different from those in healthy volunteers. In patients with severe renal insufficiency (creatinine clearance ≤ 30 ml / min) the exposure of solifenacin is much higher - an increase in CmOh is about 30%, AUC - more than 100% and t1/2 - more than 60%. There was a statistically significant relationship between creatinine clearance and solifenacin clearance. The pharmacokinetics in patients undergoing hemodialysis have not been studied.

    Liver failure: In patients with moderate hepatic insufficiency (stage B according to the Child-Pugh classification), the value of CmOh does not change, AUC increases by 60%, t1/2 doubled. Pharmacokinetics in patients with severe hepatic insufficiency was not determined.

    Indications:

    Symptomatic treatment of urinary incontinence, rapid urination and urgent urge to urinate in patients with the syndrome of hyperactive bladder.

    Contraindications:

    - Delayed urination;

    - severe gastrointestinal diseases (including toxic megacolon);

    - Myasthenia gravis;

    - an angle-closure glaucoma;

    - hypersensitivity to the active substance or any of the excipients;

    - Hemodialysis;

    severe hepatic impairment;

    - Severe renal insufficiency or moderate-level liver failure with simultaneous treatment with strong inhibitors of the CYP3A4 isoenzyme, such as ketoconazole (see the section "Interaction with other drugs");

    - Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

    - Children under 18 years.

    Carefully:

    Before starting treatment with Vesicare®, you should determine whether there are other causes of urination (heart failure or kidney disease).If an infection of the urinary tract is detected, appropriate antibiotic treatment should be initiated.

    Vesicare® should be administered with caution to patients:

    - with clinically significant bladder outlet obstruction leading to a risk of developing urinary retention;

    - with gastrointestinal diseases with obstruction;

    - with the risk of decreased motor activity of the gastrointestinal tract;

    - with severe renal (creatinine clearance <30 mL per minute) and moderate hepatic impairment (Child-Pugh Stage B); Doses for these patients should not exceed 5 mg;

    - simultaneously taking a strong inhibitor of isoenzyme CYP3A4, for example, ketoconazole;

    - with hernia of the esophagus of the diaphragm, gastroesophageal reflux and patients taking medications simultaneously (for example, bisphosphonates), which can cause or intensify esophagitis;

    - with autonomic neuropathy.

    Pregnancy and lactation:

    There are no clinical data on women who became pregnant while taking solifenacin. Studies in animals have not revealed a direct adverse effect on fertility, development of the embryo / fetus or childbirth.Care should be taken when prescribing this drug to pregnant women only if the potential benefit to the mother exceeds the potential risk to the fetus.

    There is no data on the excretion of solifenacin in breast milk. In mice solifenacin and / or its metabolites were excreted into breast milk and caused a dose-dependent developmental disorder in neonatal mice. The use of Vesicare® is not recommended during breastfeeding.

    Dosing and Administration:

    Adults, including the elderly

    5 mg once a day inside, whole, with a liquid, regardless of the time of meal. If necessary, the dose may be increased to 10 mg once a day.

    Children

    The safety and efficacy of Vesicare® in children has not been studied. Therefore, do not use Vesicare® in children.

    Patients with renal insufficiency

    No dose adjustment is required in patients with mild or moderate renal insufficiency (creatinine clearance> 30 mL / min). Patients with severe renal insufficiency (creatinine clearance ≤ 30 ml / min) solifenacin should be administered with caution and should not be prescribed more than 5 mg per day.

    Patients with hepatic insufficiency

    No dosage adjustment is required in patients with mild hepatic insufficiency. Patients with moderate hepatic insufficiency (stage B according to the Child-Pugh classification) solifenacin should be administered with caution and should not be prescribed more than 5 mg per day.

    Patients receiving strong inhibitors of isoenzyme CYP3A4

    The maximum dose of Vesicare® should be limited to 5 mg when taken together with ketoconazole or a therapeutic dose of another isoenzyme inhibitor CYP3A4 (ritonavir, nelfinavir, itraconazole).

    Side effects:

    Vesicare® may cause side effects associated with the anticholinergic effect of solifenacin, usually of mild or moderate severity. The frequency of these undesirable effects depends on the dose. The most frequently reported side effect of Vesicare® is dry mouth. It was observed in 11% of patients receiving a dose of 5 mg per day, in 22% of patients receiving a dose of 10 mg per day, and in 4% receiving a placebo. The severity of dryness in the mouth was usually weak and only rarely resulted in interruption of treatment. In general, adherence to treatment (compliance) was very high.About 90% of the patients receiving Vesicare® completed the 12-week course completely.

    The table below shows the remaining side effects reported in the Vesicare® clinical trials:

    Very Frequent >1/10

    Frequent

    (>1/100,<1/10)

    Infrequent

    (>1/1000, <1/100)

    Rare

    (>1/10000, <1/1000)

    Very rare

    <1/10000

    Unknown (frequency can not be set from available data)

    Immune system disorders

    anaphylactic reactions *

    Disorders from the metabolism and nutrition

    decreased appetite *, hyperkalemia

    Violations

    psyche

    hallucinations *, confusion *

    delirium *

    Disorders from the gastrointestinal tract

    dry mouth

    constipation, nausea, dyspepsia, abdominal pain

    gastroesophageal reflux disease, dry pharynx

    colonic obstruction, coprostasis, vomiting *

    ileus *, abdominal discomfort *

    Disturbances from the liver and bile ducts

    impairment of liver function *, change in indicators of functional liver tests *

    Infectious and parasitic diseases

    urinary tract infection, cystitis

    Disturbances from the nervous system

    drowsiness, dysgeusia (a taste disorder)

    dizziness *, headache *

    Disturbances on the part of the organ of sight

    blurred vision (violation of accommodation)

    dry eyes

    glaucoma*

    Heart Disease

    ventricular tachycardia of the type "pirouette" *, lengthening of the interval QT (ECG) *, atrial fibrillation *, tachycardia *, palpitations *

    General condition disorders

    fatigue, peripheral edema

    Disturbances of the respiratory system, chest and mediastinal organs

    dryness of the nasal cavity

    dysphonia*

    Disturbances from the skin and subcutaneous tissues

    dry skin

    rash *, itching *

    erythema multiforme *, urticaria *, angioedema *

    exfoliative dermatitis *

    Disturbances from musculoskeletal and connective tissue

    muscle weakness *

    Disorders from the kidneys and urinary tract

    difficulty urinating

    retention of urine

    kidney failure *

    * observed in the postmarketing period

    Reporting of undesirable phenomena

    Reports of alleged adverse events after authorization of the drug on the market are very important, as the company conducts continuous monitoring of the risk / benefit ratio.

    Overdose:

    An overdose of solifenacin can potentially lead to severe anticholinergic effects.The highest dose of solifenacin, which was randomly given to one patient, was 280 mg for 5 hours. This dose led to a change in the mental state of the patient, but did not require hospitalization. In cases of overdose, an appointment should be made Activated carbon, gastric lavage is effective for an hour, but do not induce vomiting.

    As in cases of an overdose of other anticholinergics, the symptoms should be treated as follows:

    - with severe anticholinergic effects of central action (hallucinations, pronounced excitability) - physostigmine or carbachole;

    - with convulsions or severe excitability - benzodiazepines;

    - with respiratory failure - artificial respiration;

    - with tachycardia - beta-blockers;

    - with acute urinary retention - catheterization;

    - with mydriasis - bury in the eyes pilocarpine and / or put the patient in a dark room.

    As in the case of an overdose of other anticholinergic drugs, special attention should be paid to patients with established risk of lengthening the interval QT (i.e., hypokalemia, bradycardia, and simultaneous administration of drugs that elongate the interval QT) and patients with previously identified heart diseases (myocardial ischemia, arrhythmias, congestive heart failure).

    Interaction:

    Pharmacological interaction

    Concomitant treatment with drugs with anticholinergic properties can lead to more pronounced therapeutic and undesirable effects. After discontinuing taking solifenacin, you should take about a week break before starting treatment with another anticholinergic drug.

    The therapeutic effect can be reduced by simultaneous administration of cholinergic receptor agonists.

    Solifenacin can reduce the effect of drugs that stimulate the motility of the gastrointestinal tract, for example - metoclopramide and cisapride.

    Pharmacokinetic interaction

    Research in vitro showed that in therapeutic concentrations solifenacin does not inhibit the isoenzymes CYP1A 1/2, 2C9, 2C19, 2D6 or 3A4, isolated from the microsome of the human liver. Therefore, it is unlikely that solifenacin will change the clearance of drugs metabolized by these CYP-enzymes.

    The effect of other drugs on the pharmacokinetics of solifenacin

    Solifenacin is metabolized by the isoenzyme CYP3A4. Simultaneous administration of ketoconazole (200 mg per day), a strong inhibitor of the isoenzyme CYP3A4, caused a two-fold increase in the AUC concentration-time dependence of solifenacin, and at a dose of 400 mg / day, a three-fold increase. Therefore, the maximum dose of Vesicare® should not exceed 5 mg if the patient simultaneously takes ketoconazole or therapeutic doses of other strong inhibitors of the CYP3A4 isoenzyme (such as ritonavir, nelfinavir, itraconazole). Simultaneous treatment with solifenacin and a strong inhibitor of the isoenzyme CYP3A4 is contraindicated in patients with severe renal failure or with moderate hepatic insufficiency.

    The phenomena of induction of enzymes on the pharmacokinetics of solifenacin and its metabolites, as well as the influence of high affinity isoenzyme substrates CYP3A4 on the action of solifenacin. Because the solifenacin is metabolized by isoenzyme CYP3A4, pharmacokinetic interactions with other isoenzyme substrates are possible CYP3A4 with a higher affinity (verapamil, diltiazem) and with isoenzyme inducers CYP3A4 (rifampicin, phenytoin, carbamazepine).

    Effect of solifenacin on the pharmacokinetics of other drugs

    Oral contraceptives:

    There was no pharmacokinetic interaction between solifenacin and combined oral contraceptives (ethinyl estradiol / levonorgestrel).

    Warfarin:

    The use of Vesicare® did not cause changes in pharmacokinetics R-warfarin or S-varfarin or their influence on prothrombin time.

    Digoxin:

    The use of Vesicare® had no effect on the pharmacokinetics of digoxin.

    Special instructions:

    In patients with such risk factors as the existing lengthening interval QT and hypokalemia, lengthening of the interval was observed QT and ventricular tachycardia of the "pirouette" type.

    Efficacy and safety have not been studied in patients with neurogenic bladder dysfunction.

    Several cases of angioedema have been reported with airway obstruction in patients taking solifenacin. Therefore, when an angioedema develops, solifenacin should be discontinued and appropriate measures taken.

    Several cases of anaphylactic reactions have been reported in patients taking solifenacin. Therefore, if there is an anaphylactic reaction, taking solifenacin should be stopped and appropriate measures taken.

    Effect on the ability to drive transp. cf. and fur:

    Solifenacin, like other anticholinergic drugs, can cause blurred vision, and (rarely) drowsiness and fatigue, which can adversely affect the ability to drive and work with machinery.

    Form release / dosage:

    Tablets, film-coated, 5 and 10 mg.

    Packaging:

    10 tablets in a blister made of polyvinyl chloride film and aluminum foil.

    For 1 or 3 blisters together with instructions for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature not higher than 25 ° C, out of the reach of children.

    Shelf life:

    3 years.

    The drug should not be used after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-000687
    Date of registration:05.07.2010 / 14.04.2014
    Expiration Date:Unlimited
    The owner of the registration certificate:Astellas Farma Europe BVAstellas Farma Europe BV Netherlands
    Manufacturer: & nbsp
    Representation: & nbspASTELLAS PHARMA YUROP BV ASTELLAS PHARMA YUROP BV Netherlands
    Information update date: & nbsp03.02.2017
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