Solifenacin-Farmak film-coated tablets 5 mg No. 100

Instructions for Solifenacin-Farmak film-coated tablets 5 mg No. 100

Composition

active ingredient: solifenacin succinate;

1 tablet contains 5 mg or 10 mg of solifenacin succinate, corresponding to 3.8 mg and 7.5 mg of solifenacin, respectively;

excipients: lactose monohydrate, lactose anhydrous, corn starch, talc, magnesium stearate;

composition of the shell for 5 mg tablets: Opadry yellow 0Y32823 (hypromellose, titanium dioxide (E 171), macrogol, red iron oxide (E 172), yellow iron oxide (E 172));

for 10 mg tablets: Opadry white 03B28796 (hypromellose, titanium dioxide (E 171), macrogol 400), Opadry brown 02F23883 (hypromellose, titanium dioxide (E 171), macrogol 6000, red iron oxide (E 172), yellow iron oxide (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: 5 mg tablets are yellow, round, biconvex, film-coated; 10 mg tablets are pink, round, biconvex, film-coated.

Pharmacotherapeutic group

Drugs used in urology. Drugs for the treatment of frequent urination and urinary incontinence. ATX code G04B D08.

Pharmacological properties

Pharmacodynamics.

Solifenacin is a competitive, specific antagonist of cholinergic receptors. The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle by acting on muscarinic receptors, which are predominantly of the M3 subtype.

In vitro and in vivo studies have shown that solifenacin is a competitive, specific antagonist of cholinergic receptors, predominantly of the M3 subtype. It has also been shown that solifenacin has little or no affinity for other receptors and ion channels tested.

The efficacy of the drug, which was studied in several double-blind, randomized, controlled clinical trials in men and women with overactive bladder syndrome, was observed as early as the 1st week of treatment and stabilized over the next 12 weeks of treatment. In open-label studies with long-term use, efficacy was shown to be maintained for at least 12 months. Pharmacokinetics.

Absorption. After taking the tablets, the maximum concentration of solifenacin in the blood plasma (Cmax) is reached after 3-8 hours. The time to reach the maximum concentration (tmax) does not depend on the dose of the drug. The Cmax and area under the curve (AUC) indicators increase proportionally to the dose in the range from 5 mg to 40 mg. Absolute bioavailability is approximately 90%. Food intake does not affect the Cmax and AUC values of solifenacin.

Distribution: Solifenacin is extensively (almost 98%) bound to plasma proteins, primarily α1-acid glycoprotein.

Metabolism: Solifenacin is extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4). The systemic clearance of solifenacin is approximately 9.5 l/h, and its terminal half-life is 45–68 hours. After oral administration, 1 pharmacologically active (4R-hydroxysolifenacin) and 3 inactive metabolites (N-glucuronide, N-oxide, and 4R-hydroxy-N-oxide of solifenacin) have been identified in plasma in addition to solifenacin.

Excretion: After a single dose of 10 mg of 14C-labeled solifenacin, approximately 70% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 11% of the radioactivity is excreted in the urine as unchanged active substance; approximately 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as the 4R-hydroxymetabolite (active metabolite).

Dose dependence. In the therapeutic dose range, the pharmacokinetics of the drug are linear.

Features of pharmacokinetics in certain categories of patients.

Age. No dose adjustment is necessary based on age. Studies have shown that exposure to solifenacin (5 and 10 mg), as expressed by AUC, was similar in healthy elderly volunteers (65 to 80 years) and healthy young and middle-aged volunteers (< 55 years). The mean rate of absorption, as expressed by tmax, was slightly slower and the terminal half-life was approximately 20% longer in elderly patients. These small differences are not clinically relevant.

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

Gender: The pharmacokinetics of solifenacin are independent of the patient's gender.

Race: Race does not affect the pharmacokinetics of solifenacin.

Renal impairment. AUC and Cmax of solifenacin in patients with mild and moderate renal impairment are not significantly different from those in healthy volunteers. In patients with severe renal impairment (creatinine clearance < 30 ml per minute), solifenacin exposure is significantly higher: the increase in Cmax is approximately 30%, AUC is more than 100% and the half-life is more than 60%. A statistically significant relationship between creatinine clearance and solifenacin clearance was observed. Pharmacokinetics in patients undergoing hemodialysis have not been studied.

Hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), Cmax is unchanged, AUC is increased by 60%, and half-life is doubled. Pharmacokinetics in patients with severe renal impairment have not been studied.

Indication

Symptomatic treatment of urge incontinence and/or frequent urination, as well as the urge to urinate, typical of patients with overactive bladder syndrome.

Contraindication

The drug is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients; in patients with urinary retention; in severe gastrointestinal diseases (including toxic megacolon); in myasthenia gravis or angle-closure glaucoma and patients at risk of developing these conditions; in patients undergoing hemodialysis (see section "Pharmacokinetics"); in patients with severe hepatic insufficiency (see section "Pharmacokinetics"); in patients with severe renal insufficiency or moderate hepatic insufficiency who are being treated with strong inhibitors of cytochrome CYP3A4, such as ketoconazole (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other types of interactions

Pharmacological interactions.

Concomitant administration of other drugs with anticholinergic properties may have more pronounced therapeutic effects, as well as undesirable consequences. After discontinuation of Solifenacin-Farmak, an interval of approximately one week should be observed before taking the next anticholinergic therapy drugs. The therapeutic effect of solifenacin may be reduced with concomitant use of cholinergic receptor agonists. Solifenacin may reduce the effect of drugs that stimulate gastrointestinal peristalsis, such as metoclopramide and cisapride.

Pharmacokinetic interactions.

In vitro studies have shown that solifenacin does not inhibit hepatic microsomal CYP1A1/2, 2C9, 2C19, 2D6 or 3A4 at therapeutic concentrations. Therefore, it is unlikely that solifenacin will affect the clearance of drugs metabolized by CYP enzymes.

Effect of other drugs on the pharmacokinetics of solifenacin.

Solifenacin is metabolized by CYP3A4. Concomitant administration of ketoconazole (200 mg/day), a strong CYP3A4 inhibitor, resulted in a two-fold increase in solifenacin AUC, while ketoconazole at a dose of 400 mg/day increased solifenacin AUC by a factor of 3. Therefore, the maximum dose of Solifenacin-Farmak should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors (e.g. ritonavir, nelfinavir, itraconazole) (see section 4.2).

Concomitant use of solifenacin and a strong CYP3A4 inhibitor is contraindicated in patients with severe renal or moderate hepatic impairment.

The effect of CYP3A4 inducers on the pharmacokinetics of solifenacin and its metabolites, as well as the effect of high-affinity CYP3A4 substrates and CYP3A4 metabolites on solifenacin exposure, has not been studied. Since solifenacin is metabolized by the CYP3A4 enzyme, pharmacokinetic interactions are possible with other CYP3A4 substrates with high affinity for CYP3A4 (e.g. verapamil, diltiazem) and inducers of the CYP3A4 enzyme (e.g. rifampicin, phenytoin, carbamazepine).

Effect of solifenacin on the pharmacokinetics of drugs.

Oral contraceptives.

Taking Solifenacin-Farmak does not affect the pharmacokinetic interaction of solifenacin with combined oral contraceptives (ethinyl estradiol/levonorgestrel).

Warfarin.

Taking Solifenacin-Farmak does not affect the pharmacokinetic interaction of R-warfarin or S-warfarin or their effect on prothrombin time.

Digoxin.

Taking Solifenacin-Farmak does not affect the pharmacokinetics of digoxin.

Application features

Before starting treatment with the drug, it is necessary to establish the likelihood of other causes of frequent urination (heart failure or kidney disease). If a urinary tract infection is detected, appropriate antibacterial therapy should be initiated.

The drug should be taken with caution in patients:

• with clinically significant bladder outlet obstruction leading to a risk of urinary retention;
• with gastrointestinal obstructive diseases;
• with the risk of decreased gastrointestinal motility;
• with severe renal (creatinine clearance < 30 ml per minute) and moderate hepatic (Child-Pugh score 7 to 9) insufficiency (see sections "Dosage and administration" and "Pharmacokinetics"); doses for these patients should not exceed 5 mg;
• with simultaneous use of strong CYP3A4 inhibitors, such as ketoconazole (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”);
• with hiatal hernia and/or gastroesophageal reflux and/or those taking concomitant medications (such as bisphosphonates) that may cause or exacerbate esophagitis;
• with autonomic neuropathy.

The safety and efficacy of the drug in patients with increased sphincter activity of neurogenic origin have not been studied.

Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Angioedema with airway obstruction has been reported in some patients treated with solifenacin succinate. If angioedema occurs, solifenacin succinate should be discontinued and appropriate measures or treatment instituted.

Anaphylactic reactions have been observed in some patients treated with solifenacin succinate. If anaphylactic reactions occur, treatment with solifenacin succinate should be discontinued and appropriate measures or treatment should be initiated.

The maximum effect of the drug is achieved no earlier than after 4 weeks of therapy.

Use during pregnancy or breastfeeding

Pregnancy.

There are no clinical data on women who became pregnant while taking solifenacin. Animal studies do not indicate direct adverse effects on fertility, embryonal/fetal development or parturition. The potential risk is unknown. Caution should be exercised when using this drug in pregnant women.

Breast-feeding.

There are no data on the excretion of solifenacin in breast milk. In mice, solifenacin and/or its metabolites penetrate into milk and cause dose-dependent growth failure in newborn mice. The use of the drug Solifenacin-Farmak is not recommended during breastfeeding.

The ability to influence the reaction speed when driving or working with other mechanisms

Due to the fact that solifenacin, like other anticholinergic drugs, can cause blurred vision and, infrequently, drowsiness and increased fatigue (see section "Adverse reactions"), taking the drug may adversely affect the ability to drive a car and operate other mechanisms.

Method of administration and doses

Adults, including the elderly. The recommended dose is 5 mg of the drug once a day. If necessary, the dose can be increased to 10 mg once a day.

Patients with renal impairment. No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance > 30 ml/min). Patients with severe renal impairment (creatinine clearance ≤ 30 ml/min) should be treated with caution at a dose not exceeding 5 mg once daily (see section 5.2).

Patients with hepatic impairment. No dose adjustment is required for patients with moderate hepatic impairment. Patients with moderate hepatic impairment (Child-Pugh score 7–9) should be treated with caution and should not exceed a dose of 5 mg once daily (see Pharmacokinetics).

Use of potent cytochrome P450 3A4 inhibitors. The maximum dose of Solifenacin-Farmak should be limited to 5 mg when co-administered with ketoconazole or therapeutic doses of other potent inhibitors of the cytochrome CYP3A4 isoform, such as ritonavir, nelfinavir, itraconazole (see section "Interaction with other medicinal products and other types of interactions").

Solifenacin-Farmak should be taken orally, swallowing the tablets whole with liquid, regardless of meals.

Children

The safety and efficacy of the drug in children have not been studied, therefore Solifenacin-Farmak should not be prescribed to this category of patients.

Overdose

Symptoms.

Overdose of solifenacin succinate can lead to severe anticholinergic effects. The highest dose of solifenacin succinate accidentally taken by one patient was 280 mg over 5 hours, resulting in mental status changes that did not require hospitalization.

Treatment: In case of overdose with solifenacin succinate, the patient should be given activated charcoal. Gastric lavage may be useful if performed within 1 hour of ingestion, but vomiting should not be induced.

Regarding other anticholinergic effects, symptoms should be treated as follows:

• severe anticholinergic effects on the central nervous system, such as hallucinations or increased excitability - physostigmine or carbachol are used;
• convulsions or increased excitability – administer a benzodiazepine;
• respiratory failure – artificial ventilation of the lungs is performed;
• tachycardia – beta-blockers are used;
• urinary retention – catheterization is performed;
• Mydriasis – use eye drops, such as pilocarpine, and/or place the patient in a dark room.

As with overdose with other anticholinergics, special attention should be paid to patients with an established risk of QT prolongation (hypokalemia, bradycardia, concomitant use of drugs that prolong the QT interval) and patients with cardiac disease (myocardial ischemia, arrhythmias, congestive heart failure).

Side effects

The most common adverse event was dry mouth, which occurred in 11% of patients receiving 5 mg/day, 22% of patients receiving 10 mg/day, and 4% of patients receiving placebo. The severity of dry mouth was generally mild and only rarely led to discontinuation of treatment. The drug was generally well tolerated (approximately 99%), and approximately 90% of patients took the drug for the full 12-week study period.

The table below lists other side effects reported during clinical trials of Solifenacin-Farmak and in the post-marketing period.

*Post-registration period.

Expiration date

4 years.

Storage conditions

The medicine does not require any special storage conditions. Keep out of the reach of children.

Packaging

10 tablets in a blister, 3 or 10 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Saneka Pharmaceuticals JSC.

Location of the manufacturer and its business address.

Nitra 100, 920 27 Hlohovec, Slovak Republic.

Applicant.

JSC "Farmak".

Location of the applicant. Ukraine, 04080, Kyiv, Kyrylivska St., 63.