Solixa Xanthis, 10 mg 30 pcs

Indications

Symptomatic treatment of urinary incontinence, frequent urination and urinary urgency in patients with overactive bladder syndrome.

Pharmacological effect

Pharmacotherapeutic group: drugs for the treatment of frequent urination and urinary incontinence, antispasmodic.

ATX CODE: G04BD08

Pharmacological properties

Mechanism of action

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

Pharmacodynamics

The clinical effect of solifenacin in doses of 5 mg and 10 mg is observed already during the first week of treatment and stabilizes over the next 12 weeks of treatment. Effectiveness lasts for at least 12 months. The maximum effect of solifenacin is observed 4 weeks after the start of therapy.

Pharmacokinetics

Absorption: maximum plasma concentration (Cmax) is reached after 3-8 hours. The time to reach maximum concentration (Tmax) is independent of dose. Cmax and area under the curve (AUC) of concentration versus time increase in proportion to increasing doses from 5 to 40 mg. Absolute bioavailability – 90%. Food intake does not affect the Cmax and AUC of solifenacin.

Distribution: The volume of distribution of solifenacin after intravenous administration is approximately 600 L. Solifenacin is highly (about 98%) bound to plasma proteins, predominantly to α1-acid glycoprotein.

Metabolism: solifenacin is extensively metabolized by the liver, predominantly by the CYP3A4 isoenzyme. However, there are alternative metabolic pathways through which solifenacin can be metabolized. The systemic clearance of solifenacin is approximately 9.5 L/hour, and the terminal half-life is 45-68 hours. After oral administration of the drug in plasma, in addition to solifenacin, the following metabolites were identified: one pharmacologically active
(4R-hydroxysolifenacin) and three inactive ones (N-glucuronide, N-oxide and 4R-hydroxy-
Solifenacin N-oxide).

Elimination: after a single administration of 10 mg of 14C-labeled solifenacin after
After 26 days, about 70% of the radioactivity was detected in urine and 23% in feces. In urine, approximately 11% of the radioactivity was found as unchanged active substance, about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxy metabolite (the active metabolite). The pharmacokinetics of solifenacin is linear over the therapeutic dose range.

Features of pharmacokinetics in certain categories of patients

Age: There is no need to adjust the dose depending on the patient’s age. Studies have shown that solifenacin (5 and 10 mg) exposure, expressed as AUC, was similar in healthy elderly volunteers (65 to 80 years) and healthy young volunteers (<55 years).

The mean absorption rate, expressed as Tmax, was slightly lower and the terminal half-life approximately 20% longer in older adults. These minor differences are not clinically significant.

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

Gender: The pharmacokinetics of solifenacin does not depend on the gender of the patient.

Race: Race does not affect the pharmacokinetics of solifenacin.

Renal failure: The AUC and Cmax of solifenacin in patients with mild to moderate renal failure are not significantly different from the corresponding values ​​in healthy volunteers. In patients with severe renal failure (creatinine clearance <30 ml/min), the exposure to solifenacin is significantly higher - the increase in Cmax is about 30%, AUC is more than 100% and
T1/2 – more than 60%. There was a statistically significant relationship between creatinine clearance and solifenacin clearance. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Liver failure: In patients with moderate liver failure (stage B according to the Child-Pugh classification), the Cmax value does not change, AUC increases by 60%, T1/2 doubles. Pharmacokinetics in patients with severe hepatic impairment have not been determined.

Special instructions

QT prolongation and torsade de pointes (TdP) have been observed in patients with risk factors such as existing QT prolongation and hypokalemia. Efficacy and safety have not been studied in patients with neurogenic bladder dysfunction. Several cases of angioedema with airway obstruction have been identified in patients taking solifenacin. Therefore, if angioedema occurs, solifenacin should be discontinued and appropriate measures taken.

Several cases of anaphylactic reactions have been identified in patients taking solifenacin. Therefore, if an anaphylactic reaction occurs, solifenacin should be discontinued and appropriate measures taken.

Influence on the ability to drive vehicles and machinery

Solifenacin, like other anticholinergic drugs, may cause blurred vision and (rarely) drowsiness and fatigue, which may impair the ability to drive and operate machines.

Active ingredient

Solifenacin

Composition

1 film-coated tablet, 10 mg contains:

active ingredient:

solifenacin succinate – 10.00 mg;

excipients:

lactose monohydrate – 110.50 mg,

corn starch – 30.00 mg,

talc – 3.00 mg,

magnesium stearate – 1.50 mg;

film coating: opadry white 03B28796 – 3.60 mg, (hypromellose 6cP E464 – 2.2500 mg, titanium dioxide E171 – 1.1250 mg, macrogol 400 – 0.2250 mg), opadry brown 02F 23883 – 0.40 mg (hypromellose 5 cP E464 – 0.2374 mg, titanium dioxide E171 – 0.0895 mg, macrogol 6000 – 0.0475 mg, yellow iron oxide dye E172 – 0.0128 mg, red iron oxide dye E172 – 0.0128).

Pregnancy

There are no clinical data on women who became pregnant while taking solifenacin. Animal studies have shown no direct adverse effects on fertility, embryonic/fetal development or childbirth. Solifenacin can be used during pregnancy only if the benefit of therapy for the mother outweighs the potential risk to the fetus.

There is no data on the penetration of solifenacin into human breast milk. In animal studies, it was found that solifenacin and/or its metabolites were excreted into the milk of lactating mice. The use of solifenacin is contraindicated during breastfeeding.

Contraindications

urinary retention;
severe gastrointestinal diseases (including toxic megacolon);
myasthenia gravis;
angle-closure glaucoma;
hypersensitivity to solifenacin or any of the excipients;
hemodialysis;
severe liver failure;
severe renal failure or moderate liver failure during simultaneous treatment with strong inhibitors of the CYP3A4 isoenzyme, such as ketoconazole (see section “Interaction with other drugs”);
lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;
breastfeeding period (see section “Use during pregnancy and breastfeeding”)
children under 18 years of age.

With caution

Before starting solifenacin therapy, other causes of frequent urination (chronic heart failure or kidney disease) should be excluded. If a urinary tract infection is detected, appropriate antibiotic therapy should be administered. Compliance with precautions when using solifenacin is required in patients:

with clinically significant obstruction of the bladder outlet, leading to the risk of developing urinary retention;
with gastrointestinal diseases with obstruction;
with a risk of reduced gastrointestinal motility;
with severe renal failure (creatinine clearance <30 ml per minute) and moderate liver failure (Child-Pugh stage B); Doses for these patients should not exceed 5 mg; while taking a strong inhibitor of the CYP3A4 isoenzyme, for example, ketoconazole; with a hiatal hernia, gastroesophageal reflux, or patients concomitantly taking medications (for example, bisphosphonates) that can cause or worsen esophagitis; with autonomic neuropathy;

in women during pregnancy (see section “Use during pregnancy and breastfeeding”).

Side Effects

The use of solifenacin may cause adverse reactions associated with its anticholinergic effect, often of mild or moderate severity. The frequency of these adverse reactions depends on the dose of solifenacin. The most commonly reported adverse reaction of solifenacin 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 placebo. The severity of dry mouth was usually mild and only in rare cases led to treatment interruption.

Immune system disorders: anaphylactic reactions

Metabolic and nutritional disorders: loss of appetite, hyperkalemia

Mental disorders: hallucinations, confusion, delirium

Gastrointestinal disorders: dry mouth, constipation, nausea, dyspepsia, abdominal pain, gastroesophageal reflux disease, dry pharynx, colonic obstruction, coprostasis, vomiting, ileus, abdominal discomfort

Disorders of the liver and biliary tract: liver dysfunction, changes in liver function tests

Infectious and parasitic diseases: urinary tract infection, cystitis

Nervous system disorders: drowsiness, dysgeusia (taste disturbance), dizziness, headache

Visual disorders: blurred vision (impaired accommodation), dry mucous membrane of the eyes, glaucoma

Cardiac disorders: ventricular tachycardia of the “pirouette” type, prolongation of the QT interval (ECG), atrial fibrillation, tachycardia, palpitations

General disorders and administration site disorders: fatigue, peripheral edema

Disorders of the respiratory system, chest and mediastinal organs: dry nasal cavity, dysphonia

Skin and subcutaneous tissue disorders: dry skin, rash, itching, erythema multiforme, urticaria, angioedema, exfoliative dermatitis

Musculoskeletal and connective tissue disorders: muscle weakness

Renal and urinary tract disorders: difficulty urinating, urinary retention, renal failure

Interaction

Pharmacological interaction

Concomitant treatment with drugs with anticholinergic properties may lead to more pronounced pharmacological effects and adverse reactions. After stopping solifenacin, take approximately a week off before starting treatment with another anticholinergic drug. The pharmacological effect may be reduced by concomitant use of cholinergic receptor agonists. Solifenacin may reduce the effect of drugs that stimulate gastrointestinal motility, such as metoclopramide.

Pharmacokinetic interaction

In vitro studies have shown that at therapeutic concentrations solifenacin does not inhibit the isoenzymes CYP1A1/2, 2C9, 2C19, 2D6 or ZA4 isolated from human liver microsomes. Therefore, solifenacin is unlikely to alter the clearance of drugs metabolized by these CYP enzymes.

Effect of other drugs on the pharmacokinetics of solifenacin

Solifenacin is metabolized by the CYP3A4 isoenzyme. Co-administration of ketoconazole (200 mg per day), a strong inhibitor of the CYP3A4 isoenzyme, caused a two-fold increase in the AUC of the concentration-time dependence of solifenacin, and at a dose of 400 mg/day – a three-fold increase. Therefore, the maximum dose of solifenacin should not exceed 5 mg if the patient is concomitantly taking ketoconazole or therapeutic doses of other strong CYP3A4 inhibitors (such as ritonavir, nelfinavir, itraconazole). The combined use of solifenacin and strong inhibitors of the CYP3A4 isoenzyme is contraindicated in patients with severe renal impairment or moderate hepatic impairment. The phenomena of enzyme induction on the pharmacokinetics of solifenacin and its metabolites, as well as the influence of high-affinity substrates of the CYP3A4 isoenzyme on the action of solifenacin, have not been studied.

Since solifenacin is metabolized by the CYP3A4 isoenzyme, pharmacokinetic interactions with other CYP3A4 isoenzyme substrates with higher affinity (verapamil, diltiazem) and with CYP3A4 isoenzyme inducers (rifampicin, phenytoin, carbamazepine) are possible.

Effect of solifenacin on the pharmacokinetics of other drugs

Oral contraceptives: no pharmacokinetic interaction has been identified between solifenacin and combined oral contraceptives (ethinyl estradiol + levonorgestrel).

Warfarin: Solifenacin did not cause changes in the pharmacokinetics of R-warfarin or S-warfarin or their effect on prothrombin time.

Digoxin: Solifenacin had no effect on the pharmacokinetics of digoxin.

Overdose

Overdose of solifenacin can potentially lead to severe anticholinergic effects. The highest dose of solifenacin that was accidentally taken by one patient was 280 mg over 5 hours. This dose resulted in a change in the patient’s mental status but did not require hospitalization. In cases of overdose, activated charcoal should be prescribed, gastric lavage is effective for an hour, but vomiting should not be induced. As with overdose of other anticholinergic drugs, symptoms should be treated as follows:

for severe anticholinergic effects of central action (hallucinations, severe excitability) – carbachol;
for convulsions or severe excitability – benzodiazepines;
in case of respiratory failure – artificial respiration;
for tachycardia – beta blockers;
for acute urinary retention – catheterization;
for mydriasis, instill pilocarpine into the eyes and/or place the patient in a dark room.

As with overdose of other anticholinergic drugs, special attention should be paid to patients with an established risk of QT prolongation (i.e., hypokalemia, bradycardia, and concomitant use of drugs known to prolong the QT interval) and patients with previously diagnosed cardiac disease (myocardial ischemia, arrhythmias, chronic heart failure).

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

4 years.
Do not use after expiration date.

Manufacturer

Saneka Pharmaceuticals a.s., Slovakia