Vesomni® [Solifenacin Succinate, Tamsulosin]

Pharmacological properties

Vesomni is a combined preparation containing two active substances - solifenacin and tamsulosin. these active substances have independent and complementary mechanisms of influence for the treatment of symptoms of the lower urinary tract (CPS), benign prostatic hyperplasia (BPH), and symptoms of bladder filling.

Solifenacin is a selective competitive antagonist of muscarinic receptors; it does not have an affinity for other receptors, enzymes, or ion channels. Solifenacin has a high affinity for muscarinic M₃-receptors, and less affinity for muscarinic M₁ them₂to receptors.

Tamsulosin - α blocker₁-adrenoreceptors. Tamsulosin selectively and competitively binds to postsynaptic α₁-adrenoreceptors, especially with subtypes α₁A and α₁D, responsible for the relaxation of the smooth muscles of the lower urinary tract.

Solifenacin relieves symptoms of bladder filling (irritative symptoms) associated with the action of acetylcholine, which activates M₃cholinergic receptors in the bladder. Acetylcholine activates the contractile function of the bladder wall, which manifests itself in the form of urgent urges to urinate or urinary incontinence.

Tamsulosin improves the symptoms of emptying, increasing the maximum flow rate of urine, reduces the severity of symptoms of obstruction, relaxing the smooth muscles of the prostate gland, bladder neck and urethra. Also improves urine filling of the bladder.

Pharmacokinetics A study of bioavailability with multiple doses showed that the pharmacokinetics when using the Vesomni drug are compared with pharmacokinetics while taking solifenacin and tamsulosin.

Suction. After taking Vesomni repeatedly, the time to reach C_max (t_max) for solifenacin varies between 4.27 and 4.76 hours in various studies, for tamsulosin - 3.47–5.65 hours, respectively. C_max for solifenacin ranged between 26.5 and 32.0 ng / ml, for tamsulosin - between 6.56 and 13.3 ng / ml. The AUC value for solifenacin ranged from 528 to 601 ng / h / ml, and tamsulosin ranged from 97.1 to 222 ng / h / ml. The bioavailability of solifenacin was about 90%, while tamsulosin is absorbed by 70–79% of the applied dose.

A study was carried out on the use of Vesomni in a single dose at the same time as eating, while eating a low-fat meal, eating a low-calorie breakfast, and while eating a high-fat and high-calorie breakfast. After eating a high-fat, high-calorie breakfast, an increase in C_max for tamsulosin by 54% compared with fasting, in which AUC is increased by 33%. The pharmacokinetics of solifenacin does not change with a low-fat meal, a low-calorie breakfast, and a high-fat meal with a high-calorie breakfast.

Concomitant use of solifenacin and tamsulosin OCAS leads to an increase in C_max by 1.19 times and an increase in AUC of tamsulosin by 1.24 times compared with AUC of tamsulosin OCAS with monotherapy. There are no indicators of the effect of tamsulosin on the pharmacokinetics of solifenacin.

After a single dose of Vesomni T_½ solifenacin ranged from 49.5 to 53 hours; tamsulosin - from 12.8 to 14 hours

Repeated use of verapamil in a dose of 240 mg at the same time as Vesomni leads to an increase in C_max solifenacin by 60% and an increase in AUC by 63%, while for tamsulosin C_max rises to 115% and AUC increases to 122%. C changes_max and AUC are not clinically significant.

The results of the analysis of pharmacokinetic data during the third phase of clinical studies indicate the variability of the pharmacokinetics of tamsulosin depending on the age, growth and concentration in the blood of α₁-acid glycoprotein. An increase in AUC is associated with an increase in α₁-acid glycoprotein and age, while a decrease in AUC is associated with decreased growth. In addition, an increase in gamma-glutamyl transpeptidase levels is associated with high AUC. These changes in AUC are not clinically significant.

Information on the pharmacokinetics of the active substances of the combined drug is supplemented by the pharmacokinetic properties of the drug Vesomni.

Solifenacin

Suction. Time to reach C_max (t_max) does not depend on the dose and ranges from 3 to 8 hours after taking several doses. C values_max and AUC increase in proportion to the dose of 5 to 40 mg. Bioavailability is approximately 90%.

Distribution. The volume of distribution of solifenacin after iv administration of the drug is about 600 liters. Approximately 98% of solifenacin binds to plasma proteins, primarily to α₁-acid glycoprotein.

Metabolism. Solifenacin is metabolized slowly, has a low first-pass effect. Solifenacin is actively metabolized in the liver, mainly with the participation of CYP 3A4. However, there are alternative metabolic pathways that can affect solifenacin metabolism. The systemic clearance of solifenacin is about 9.5 l / h. After administration in plasma, one pharmacologically active metabolite (4R-hydroxysolifenacin) and three inactive metabolites (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide of solifenacin) were determined (in addition to solifenacin).

After a single dose of 10 mg ¹⁴About 70% of radioactivity of C-labeled solifenacin was detected in urine and 23% in feces within 26 days. In urine, approximately 11% of the radioactivity is determined unchanged in the form of the active substance, about 18% as the N-oxide metabolite, 9% as the 4R-hydroxy-N-oxide metabolite, and 8% as 4R-hydroxymetabolite (active metabolite).

Tamsulosin

Suction. For tamsulosin in the form of OCAS, t_max is in the range from 4 to 6 hours after several doses of 0.4 mg / day. C_max and AUC increase in proportion to the dose from 0.4 to 1.2 mg. Bioavailability is approximately 57%.

Distribution. The volume of distribution of tamsulosin after iv administration is about 16 liters. Approximately 99% of tamsulosin binds to blood plasma proteins, primarily α₁-acid glycoprotein.

Metabolism. Tamsulosin has a low first-pass effect, is metabolized slowly. Tamsulosin is actively metabolized in the liver, mainly with the participation of CYP 3A4 and CYP 2D6. Systemic clearance of tamsulosin is about 2.9 l / h. Most of the used tamsulosin is present in the blood plasma as an unchanged active substance.

None of the metabolites was more active than the starting material.

In the case of a single dose of 0.2 mg ¹⁴After 1 week of treatment, about 76% of the radioactivity of C-labeled tamsulosin is excreted in the urine and 21% in the feces. About 9% of the radioactivity in unchanged form in the form of the active substance was detected in urine, about 16% - in the form of o-diethylated tamsulosin sulfate and 8% - as o-ethoxyphenoxyl-acetic acid.

Characteristics in special patient groups

Elderly patients. In studies of clinical pharmacology and bioavailability, the age of patients ranged from 19 to 79 years. After the use of the drug Vesomni, high concentrations were found in the elderly, although there was almost complete coincidence with individual indicators in younger patients. The drug Vesomni can be used in the elderly.

Renal failure. Vesomni is used in patients with mild to moderate renal failure, but caution should be exercised when used in patients with severe renal failure.

The pharmacokinetics of Vesomni has not been studied in patients with renal failure.

The following data reflect information on renal failure characteristic of each of the active ingredients of the drug.

Solifenacin. AUC and C_max solifenacin in patients with mild and moderate severity of renal failure slightly differ from those in healthy volunteers.In patients with severe renal failure (creatinine clearance ≤30 ml / min), exposure to solifenacin is significantly higher - increased C_max is about 30%, AUC - 100% and T_½ - 60%. There was a statistically significant relationship between creatinine clearance and solifenacin clearance. The pharmacokinetics of hemodialysis patients have not been studied.

Tamsulosin. Tamsulosin pharmacokinetics were compared in 6 patients with mild to moderate renal failure (creatinine clearance ≥30 - 70 ml / min / 1.73 m²) or with moderate to severe renal failure (≤30 ml / min / 1.73 m²) and in 6 healthy patients (creatinine clearance ≥90 ml / min / 1.73 m²) Changes in the total concentration of tamsulosin in blood plasma due to a change in connection with α₁-acid glycoprotein, the active concentration of tamsulosin hydrochloride, as well as internal clearance, remained relatively stable. Pharmacokinetics of tamsulosin in patients with the last stage of renal failure (creatinine clearance 10 ml / min / 1.73 m²) has not been studied.

Liver failure. Vesomni is used in patients with mild to moderate hepatic insufficiency, but is contraindicated for people with severe hepatic insufficiency.

The pharmacokinetics of Vesomni has not been studied in patients with renal failure.

The following data reflect information on liver failure characteristic of each of the active ingredients of the drug.

Solifenacin. In patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale), the value of C_max does not change, AUC - increases by 60%, T_½ increases by 2 times.

Pharmacokinetics in patients with severe hepatic impairment has not been studied.

Tamsulosin. The pharmacokinetics of tamsulosin were compared in 8 patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale) and in 8 healthy patients. Changes in the total concentration of tamsulosin in blood plasma due to a change in connection with α₁-acid glycoprotein, the active concentration of tamsulosin hydrochloride did not change significantly, and the internal clearance of inactive tamsulosin changed moderately (32%). The pharmacokinetics of tamsulosin in patients with severe hepatic impairment has not been studied.

Indications

Treatment of symptoms of bladder fullness (peremptory urination, frequent urination) of moderate and severe degrees and symptoms of bladder emptying (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in men who have not been given monotherapy.

Application

Adult men, including the elderly. take orally 1 tablet of vesomni (6 mg / 0.4 mg) once a day, regardless of food intake. the maximum daily dose of vesomni is 1 tablet (6 mg / 0.4 mg). the tablets are taken whole without chewing or crushing.

Patients with renal failure. The effect of renal failure on the pharmacokinetics of the drug Vesomni has not been studied. However, the effect on the pharmacokinetics of the individual active ingredients of the drug has been well studied (see Pharmacokinetics). The drug Vesomni can be prescribed to patients with mild to moderate renal failure (creatinine clearance of 30 ml / min). Patients with severe renal failure (creatinine clearance ≤30 ml / min) should be used with caution and not exceed the maximum daily dose.

Patients with impaired liver function. The effect of liver failure on the pharmacokinetics of the drug Vesomni has not been studied. However, the effect on the pharmacokinetics of the individual active ingredients of the drug has been well studied (see Pharmacokinetics). Vesomni can be prescribed for patients with mild liver failure (Child-Pugh score ≤7).Patients with moderate liver failure (Child-Pugh score of 7–9) should use the drug with caution and not exceed the maximum daily dose. For patients with severe liver failure (Child-Pugh score of 9), the use of Vesomni is contraindicated.

Moderate and potent inhibitors of cytochrome P450 3A4. Vesomni should be used with caution in patients who are simultaneously receiving moderate or potent CYP 3A4 inhibitors (such as verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole).

Contraindications

Hypersensitivity to active substances or any of the excipients. hemodialysis. severe liver failure. severe renal failure, in which powerful cytochrome p450 (cyp) 3a4 inhibitors are used, for example ketoconazole. moderate hepatic impairment, in which powerful cyp 3a4 inhibitors, such as ketoconazole, are also used.

Severe gastrointestinal diseases (including toxic megacolon), myasthenia gravis or glaucoma and the presence of risks of developing these diseases. A history of orthostatic hypotension.

Side effects

Vesomni may cause anticholinergic adverse reactions of mild to moderate severity. the most common adverse reactions were dry mouth (9.5%), constipation (3.2%) and dyspepsia (including abdominal pain, 2.4%). often other adverse reactions were noted, such as dizziness (1.4%), blurred vision (1.2%), increased fatigue (1.2%) and impaired ejaculation (including retrograde ejaculation, 1.5%). the serious adverse reaction that was observed during the treatment with vesomni during clinical trials was acute urinary retention (0.3%, infrequently). the frequency of adverse reactions is determined as follows: very often (≥1 / 10); often (≥1 / 100 to 1/10); infrequently (≥1000 to 1/100); rarely (≥1 / 10,000 to 1/1000), very rarely (1/10 000), unknown (cannot be estimated based on available data).

^#Adverse reactions are included in this table.