VEZIKAR

Active material: Solifenacin
When ATH: G04BD08
CCF: Preparation, lowering the tone of smooth muscles of the urinary tract
ICD-10 codes (testimony): N31.2, R32, R35
When CSF: 28.02.01.01
Manufacturer: ASTELLAS PHARMA EUROPE B.V. (Netherlands)

Pharmaceutical form, composition and packaging

Pills, coated light yellow, round, lenticular, labeled “150” and the company's logo on one side.

Excipients: lactose monohydrate, corn starch, gipromelloza 3 mPa × s, magnesium stearate, Purified water.

The composition of the coating film: Opadry Yellow 03F12967 (gipromelloza 6 mPa × s, talc, macrogol 8000, Titanium dioxide, iron oxide yellow).

10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.

Pills, coated light pink, round, lenticular, labeled “151” and the company's logo on one side.

Excipients: lactose monohydrate, corn starch, gipromelloza 3 mPa × s, magnesium stearate, Purified water.

The composition of the coating film: Pink Opadry 03F14895 (gipromelloza 6 mPa × s, talc, macrogol 8000, Titanium dioxide, iron oxide red).

10 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.

Pharmacological action

Preparation, lowering the tone of smooth muscles of the urinary tract. Pharmacological studies, conducted in vitro and in vivo, shown, that solifenacin is a specific competitive inhibitor of m-cholinergic receptors, preferably M₃ subtypes. It was also found, that solifenacin has a low affinity or absence of affinity to a variety of other receptors and ion channels.

The efficacy of Vesicare^® when used in doses 5 mg 10 mg, studied in several double-blind, randomized, controlled clinical trial in men and women with overactive bladder syndrome, It is observed within the first week of treatment and stabilized over the next 12 weeks of treatment. The maximum effect of Vesicare^® It can be identified by 4 of the week. Efficiency is maintained for a long application (no less 12 Months).

Pharmacokinetics

Absorption

After oral administration, C_makh plasma levels achieved after 3-8 no. The time to maximum concentration (T_max) not dose. FROM_makh and AUC increased in proportion to the increase in dose from 5 to 40 mg. The absolute bioavailability – 90%. Eating does not affect the C_makh and AUC of solifenacin.

Pharmacokinetics of solifenacin is linear in the therapeutic dose range.

Distribution

After the on / in the V_d It is about solifenacin 600 l. The binding to plasma proteins of solifenacin, mainly with α₁-acid glycoprotein, is about 98%.

Metabolism

Solifenacin is extensively metabolised in the liver, mainly with the participation of CYP3A4. However, there are alternative pathways solifenacin. After oral administration of plasma in addition to solifenacin were identified following metabolites: one pharmacologically active 4R-gidroksisolifenatsin and three inactive – N-glucuronide, N-oxide and 4R-hydroxy-N-oxide solifenacin).

Deduction

Systemic clearance of solifenacin is about 9.5 l / h, and the final T_1/2 is 45-68 no. After a single injection 10 mg ¹⁴C-labeled solifenacin through 26 d about 70% Radioactivity was detected in urine and 23% Calais. In urine about 11% radioactivity detected as unchanged active substance, about 18% It saw in the metabolite N-oksidnogo, 9% – a 4R-hydroxy-N-oxide and solifenacin 8% – a 4R-hydroxy metabolite (active metabolite).

Pharmacokinetics in special clinical situations

There is no need to adjust the dose depending on the age of the patients. Studies have shown, that exposure solifenacin (5 and 10 mg), expressed as AUC, It was similar in healthy elderly (from 65 to 80 years) in healthy young men (to 55 years). In the elderly the average absorption rate, expressed as T_max, It was slightly lower than, and the final T_1/2 increased by approximately 20%. These minor differences are not clinically significant. Pharmacokinetics of solifenacin in children and adolescents has not been studied.

The pharmacokinetics of solifenacin are not influenced by gender and race of the patient.

In patients with renal insufficiency mild to moderate C_makh and AUC of solifenacin differ slightly from those in healthy volunteers. Patients with severe renal insufficiency (QC ≤30 mL / min) solifenacin exposure is much higher – With the increase_makh is about 30%, AUC – more 100% and T_1/2 – more 60%. There was a statistically significant relationship between spacecraft and ground clearance of solifenacin. Pharmacokinetics in Patients, undergoing hemodialysis, I have not been studied.

In patients with moderate hepatic insufficiency (from 7 to 9 points on the Child-Pugh) the value of C_makh It does not change, AUC is increased by 60%, T_1/2 increases 2 times. The pharmacokinetics in patients with severe hepatic impairment has not been studied.

Testimony

- Emergency treatment (ymperatyvnoho) Incontinence, frequent urination and urgent (peremptory) urge to urinate, characteristic of patients with overactive bladder syndrome.

Dosage regimen

The drug is prescribed inside of 5 mg 1 time / day, regardless of the meal. If necessary, the dose may be increased to 10 mg 1 time / day. The tablets should be taken with plenty of fluids.

Side effect

Vezikar^® could cause side effects, associated with anticholinergic solifenacin, usually mild or moderate severity. The frequency of these adverse effects is dose-dependent. The most frequently reported side effect of Vesicare^® – dry mouth (I observed in 11% patients, receiving the drug in a daily dose of 5 mg, in 22% patients, receiving the drug in a daily dose of 10 mg, and 4% patients, placebo). The severity of this side effect was usually mild and rarely led to discontinuation of treatment. In general, adherence (compliance) It was very high.

The following are other side effects, registered in the clinical studies on the use of Vesicare^®. We used the following criteria for evaluating the frequency of adverse events: often (>1%, <10%); sometimes (>0.1%, <1%); rarely (>0.01%, <0.1%).

From the digestive system: often – constipation, nausea, dyspepsia, abdominal pain; sometimes – gastroesophageal reflux disease, dryness of the throat; rarely – ileus, coprostasia.

From the urinary system: sometimes – urinary tract infection, difficulty urinating; rarely – acute urinary retention.

CNS: sometimes – drowsiness, disgevziya (taste disturbance).

On the part of the organ of vision: often – blurred vision (ccomodation); sometimes – dry eyes.

The respiratory system: sometimes – dryness of the nasal cavity.

Dermatological reactions: sometimes – xerosis.

Other: sometimes – fatigue, edema of the lower extremities.

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

Contraindications

- Acute and chronic urinary retention;

- Severe gastrointestinal disease (including toxic megacolon);

— myasthenia gravis;

- Zakrыtougolynaya glaucoma;

- Severe hepatic impairment;

- Severe renal impairment or moderate hepatic impairment, while the treatment of inhibitors of CYP3A4 (eg, ketoconazole);

- Hemodialysis;

- Hypersensitivity to the drug.

Pregnancy and lactation

There is no clinical data on women, who became pregnant while taking solifenacin. It should be used with caution Vesicare^® Pregnancy.

The data on the allocation of solifenacin in human breast milk are absent. The use of Vesicare^® it is not recommended during breastfeeding.

IN experimental studies in animals have not revealed a direct adverse effect on fertility, development of the embryo / fetus, or childbirth.

Cautions

Before treatment Vesicare^® to exclude other causes urination disorders. If you found a urinary tract infection, should start appropriate antibiotic therapy.

Precautions should be prescribed Vesicare^® in the following cases:

- Clinically significant bladder outlet obstruction, leading to the risk of acute urinary retention;

- Gastrointestinal obstructive disease;

- Reduce the risk of GI motility;

- Severe renal insufficiency (CC ≤ 30 ml / min) and mild hepatic impairment (from 7 to 9 points on the Child-Pugh); dose for these patients should not exceed 5 mg;

- Concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole);

- Hiatal hernia, gastroesophageal reflux disease, and concomitant use of drugs (eg, ʙisfosfonatov), that can cause or enhance the development of the symptoms of esophagitis;

- Avtonomnaya neuropathy.

Patients with rare hereditary disorders of galactose tolerance, lapp lactase deficiency (lactase deficiency, some people of the North), malabsorption of glucose-galactose should not take the drug.

Effects on ability to drive vehicles and management mechanisms

Solifenacin, like other anticholinergic drugs, It can cause blurred vision, and drowsiness (rarely) and fatigue, which may adversely affect the ability to drive and use machines.

Overdose

Symptoms: when using the drug in doses volunteers 100 mg dose most commonly observed side effects following: headache (easy), dry mouth (moderate), dizziness (moderate), drowsiness (easy) and blurred vision (moderate). No cases of acute overdose have been reported.

Treatment: In case of overdose should be appointed activated carbon, gastric lavage, but do not induce vomiting. If necessary spend symptomatic therapy:

- With severe effects of centrally acting anticholinergics (hallucinations, severe anxiety) administered physostigmine or carbachol;

- In convulsions or severe irritability – benzodiazepines;

- Respiratory failure – IVL;

- Tachycardia – beta-blockers;

- In acute urinary retention – bladder catheterization;

- When mydriasis – instilled into the eyes of pilocarpine and / or place patient in dark room.

As with other anticholinergic drugs overdose, special attention should be given to patients with established risk of QT prolongation (ie. if hypokalemia, bradycardia while taking drugs, causing QT prolongation) and patients with diseases of the cardiovascular system (myocardial ischemia, Arrhythmia, congestive heart failure).

Drug Interactions

If concomitant treatment with drugs anticholinergic properties may experience a more pronounced therapeutic effect and development of undesirable effects. After discontinuation of solifenacin should be done a week break, before starting treatment other anticholinergic drugs. The therapeutic effect may be lowered while taking nicotinic acetylcholine receptor agonists.

Solifenacin can reduce the effect of the drugs, stimulating the motility of the gastrointestinal tract, eg, metoclopramide and cisapride.

Studies in vitro have shown, at therapeutic concentrations, solifenacin does not inhibit CYP1A 1/2, 2C9, 2C19, 2D6 or 3A4. Therefore it is unlikely, change that solifenacin clearance of drugs, metabolized by these enzymes.

Solifenacin is metabolized by CYP3A4. Simultaneous administration of a dose of ketoconazole 200 mg / day, CYP3A4 inhibitor, It caused a two-fold increase in AUC of solifenacin, and in a dose 400 mg / cut – a threefold increase. Therefore, the maximum dose of Vesicare^® should not exceed 5 mg, if the patient simultaneously receives ketoconazole or therapeutic doses of other CYP3A4 inhibitors (such, how ritonavir, Nelfinavir, itraconazole). Co-administration of solifenacin and CYP3A4 inhibitor is contraindicated in patients with severe renal impairment or moderate hepatic impairment. Because solifenacin is metabolized by CYP3A4, pharmacokinetic interactions are possible with other CYP3A4 substrates with higher affinity (verapamil, diltiazem) and with CYP3A4 inducers (rifampicin, phenytoin, Carbamazepine).

There were no pharmacokinetic interaction of solifenacin and a combined oral contraceptive (ethinyl estradiol / levonorgestrel).

Simultaneous treatment of solifenacin did not cause changes in the pharmacokinetics of R-warfarin and S-warfarin or their effect on prothrombin time.

Simultaneous treatment of solifenacin had no effect on the pharmacokinetics of digoxin.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 3 outside.