Vesomni pills 6mg + 0.4mg №10

Composition

Pills

Active ingredients: solifenacin succinate 6.0 mg, Tamsulosin hydrochloride 0.4 mg,

Excipients: mannitol 83.0 mg, maltose 10.0 mg, Magnesium stearate 2.2 mg, macrogol 7 000 000 200.0 mg, macrogol 8 000 40.0 mg.

pharmachologic effect

Vesomni is a combination drug that contains two active substances, solifenacin and tamsulosin. These active substances have independent and complementary mechanisms of action in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia, in the presence of filling symptoms.
Solifenacin is a selective competitive inhibitor of the muscarinic receptors of the bladder, mainly the M3 subtype, and has low or no affinity for various other receptors, enzymes, and ion channels.
Tamsulosin is an alpha1-blocker. It is a selective competitive blocker of postsynaptic α1-adrenoreceptors, especially the α1A and α1D subtypes, which are responsible for the relaxation of the smooth muscles of the lower urinary tract.
Pharmacodynamic effects.
Solifenacin alleviates the symptoms of bladder filling (irritative symptoms) associated with the action of acetylcholine, which activates m3-cholinergic receptors in the bladder. Acetylcholine activates the contractile function of the bladder wall, which manifests itself as an urgent urge to urinate or urinary incontinence.
Tamsulosin relieves emptying symptoms (obstructive symptoms) by relaxing the smooth muscles of the prostate gland, bladder neck and the prostatic part of the urethra. Also reduces filling symptoms.
Clinical efficacy and safety.
The efficacy of the drug was demonstrated as a result of a Phase III clinical trial in patients with lower urinary tract symptoms on the background of benign prostatic hyperplasia. When Vesomny was taken, there was a statistically significant decrease in symptoms on the scale of urgent urge and frequency of urination, as well as the general frequency of urination, the average volume of urine allocated for one urination, and the IPSS-baseline score compared to tamsulose in the form of controlled release (OKAS) ).These improvements are accompanied by a significant increase in the indicator of quality of life on the IPSS scale and the indicator of quality of life according to the Questionnaire for assessing the severity of bladder hyperactivity symptoms. In addition, Vesomni was not inferior to tamsulosin OKAS in reducing symptoms when evaluating the overall score on the IPSS scale (p <0.001).
Pharmacokinetics: Absorption.
After taking Vesomni multiple times, the time to reach the maximum concentration (tmax) for solifenacin varied between 4.27 h and 4.76 h in different studies, for tamsulosin - between 3.47 h and 5.65 h, respectively. The maximum plasma concentration (Cmax) for solifenacin varied between 26.5 ng / ml and 32.0 ng / ml, for tamsulosin, between 6.56 ng / ml and 13.3 ng / ml. The area under the concentration-time curve (CPD) for solifenacin ranged from 528 ngch / ml to 601 ngch / ml, for tamsulosin, between 97.1 ngch / ml and 222 ngch / ml. Absolute bioavailability for solifenacin is about 90%, while tamsulosin is absorbed by 70-79%.
Inference.
After a single dose of Vesomni, the half-life (t1 / 2) for solifenacin varies from 49.5 hours to 53.0 hours, for tamsulosin - from 12.8 hours to 14.0 hours.
Information on the pharmacokinetics of the active substances of the combined preparation complements the pharmacokinetic properties of Vesomni:
- Solifenacin
Absorption.
The maximum concentration in plasma (Cmax) is reached in 3-8 hours. The time to reach the maximum concentration (tmax) does not depend on the dose. Сmax and the area under the concentration-time curve (CPD) concentration dependences on time increase in proportion to the dose increase from 5 to 40 mg. Absolute bioavailability - 90%.
Distribution.
The volume of distribution of solifenacin after intravenous administration is approximately 600 liters. Solifenacin is largely (about 98%) bound to plasma proteins, predominantly with an α1-acid glycoprotein.
Metabolism.
Solifenacin is actively metabolized by the liver, mainly by the 3A4 (CYP3A4) isoenzyme of the cytochrome P450 system. However, there are alternative metabolic pathways through which solifenacin may be metabolized. 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-hydroxysolifenacin) and three inactive (N-glucuronide, N-oxide and 4R-hydroxy-N-oxide solifenacin).
Withdrawal: After a single injection of 10 mg of a 14C-labeled solifenacin after 26 days, about 70% of the radioactivity was detected in the urine and 23% in the feces. In the urine, approximately 11% of the radioactivity was detected as unchanged active substance, about 18% as N-oxide metabolite, 9% as 4R-hydroxy-N-oxide metabolite, and 8% as 4R-hydroxy metabolite (active metabolite).
- Tamsulosin
Absorption.
For tamsulosin in the form of OKAS, absorption is estimated at 57% of the injected dose. Tamsulosin is characterized by linear pharmacokinetics. In equilibrium, the concentration of tamsulosin in the plasma reaches a peak after 4-6 hours.
Distribution.
Communication with plasma proteins is about 99%, the volume of distribution is small (about 0.2 l / kg).
Metabolism.
Tamsulosin is slowly metabolized in the liver to form less active metabolites. Most tamsulosin is present in plasma in unchanged form. Tamsulosin is mainly metabolized in the liver, mainly with the participation of CYP3A4 and CYP2D6 isoenzymes.
Inference.
After a single dose of 0.2 mg of 14C-labeled tamsulosin, after 1 week about 76% of the radioactivity was detected in the urine and 21% in the feces. In the urine, about 9% of the radioactivity was detected as unchanged active substance; about 16% as sulphate of o-deethyl tamsulosin, and 8% as o-ethoxyphenoxy acetic acid.
Features pharmacokinetics in certain categories of patients:
Elderly people.
In clinical pharmacology and bioavailability studies, patient age ranged from 19 to 79 years. After Vesomni was applied, the highest concentrations were found in elderly patients, although there was an almost complete coincidence with some indicators of younger patients. Vesomes can be used in older patients.
Renal failure.
The pharmacokinetics of Vesomney has not been studied for patients with renal insufficiency. The data below reflects information available for each component of the preparation regarding patients with renal insufficiency.
Solifenacin
AUC and Cmax of 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 - the Cmax increase is about 30%, the PEP - 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 has not been studied.
Tamsulosin
The pharmacokinetics of tamsulosin were compared in 6 patients with mild to moderate (30≥ creatinine clearance <70 ml / min / 1.73 m²) or moderately severe (≤30ml / min / 1.73²) renal failure and in 6 healthy patients (creatinine clearance ≥90 ml / min / 1.73 m²). While there was a change in the total concentration of tamsulosin in the blood plasma as a result of a change in association with alpha 1-acid glycoprotein, the active concentration of tamsulosin hydrochloride, as well as its own clearance, remained relatively stable. The 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:
The pharmacokinetics of Vesomnia has not been studied for patients with hepatic insufficiency. The data below reflects information available for each component of the preparation regarding patients with hepatic insufficiency.
Solifenacin
In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), the Cmax value does not change, AUC is increased by 60%, t1 / 2 is doubled. Pharmacokinetics in patients with severe hepatic insufficiency was not determined.
Tamsulosin
Tamsulosin pharmacokinetics were compared in 8 patients with moderate hepatic insufficiency (7–9 on the Child-Pugh scale) and in 8 healthy patients. While a change in total plasma concentration of tamsulosin was observed as a result of a change in association with alpha-1 acid glycoprotein, the active concentration of tamsulosin hydrochloride did not change significantly, and its own clearance of inactive tamsulosin was moderately changed (32%). The pharmacokinetics of tamsulosin in patients with severe liver failure has not been studied.

Indications

Treatment of filling symptoms (irritative symptoms), moderate to severe (urge to urinate, frequent urination), and emptying symptoms (obstructive symptoms) associated with benign prostatic hyperplasia in men who do not have an adequate response to monotherapy.

Contraindications

- hypersensitivity to the active components of the drug or to excipients
- hemodialysis
- severe liver failure
- severe renal failure or moderate liver failure with simultaneous treatment with strong inhibitors of CYP3A4 isoenzyme, for example, Ketoconazole
- the presence of severe gastrointestinal diseases (including toxic megacolon), myasthenia and angle-closure glaucoma, as well as the risks of developing these diseases.
- orthostatic hypotension
- children's and teenage age up to 18 years
Carefully.
Patients should be carefully prescribed with:
- severe renal failure,
- the risk of urinary retention,
- with gastrointestinal obstructive diseases,
- with the risk of reduced gastrointestinal motility,
- with hernia of the esophageal orifice of the diaphragm, gastroesophageal reflux, and patients who are simultaneously taking drugs (for example, bisphosphonates), which can cause or strengthen esophagitis,
- with peripheral neuropathy,
- in patients with such risk factors as the syndrome of lengthening the QT interval and hypokalemia, prolongation of the QT interval and tachycardia of the “pirouette” type were observed.

Side effects

Vesomnia can cause side effects associated with the m-anticholinergic action of solifenacin, often mild or moderate severity. The most frequently reported side effects of dry mouth (9.5%), constipation (3.2%) and dyspepsia (including 2.4% pain in the abdomen) were reported during the conduct of clinical trials with Vesomni. Other common adverse reactions include dizziness (1.4%), blurred vision (1.2%), fatigue (1.2%) and ejaculation disorders (including retrograde ejaculation - 1.5%). Acute urinary retention (0.3%, rare) is the most serious side effect that was observed during the treatment with Vesomni during clinical trials.
In the table below, the column "The frequency of adverse reactions when taking Vesomni" reflects the adverse reactions recorded during the clinical study of the drug Vesomni.
The columns “frequency of occurrence of undesirable reactions of solifenacin and tamsulosin” reflect undesirable reactions reported for individual components (data from drug instructions solifenacin 5 and 10 mg and tamsulosin 0.4 mg, respectively), and which can potentially occur when taking the drug Vesomney .
The frequency of adverse reactions is determined as follows: very often (≥1 / 10); often (≥1 / 100 to <1/10); infrequently (≥1 / 1000 to <1/100); rarely (≥1 / 10,000 to <1/1000); very rarely (<1 / 10,000), unknown (impossible to estimate based on available data).
* observed after registration of the drug. Due to the fact that the data were obtained by the method of spontaneous messages in the post-registration period, determining the frequency and causal relationship with taking tamsulosin and solifenacin is difficult.
Vesomny's long-term safety data:
The types and frequency of adverse reactions that were observed during the treatment for 1 year with Vesomni, coincided with the data that were observed during the 12-week study. The drug was well tolerated, and there were no specific adverse reactions associated with prolonged use of the drug.
Elderly people:
Side effects that occur in older people were similar in effect to younger patients.

Interaction

Interactions with inhibitors of CYP3A4 and CYP2D6.

The simultaneous use of solifenacin ketoconazole (a potent CYP3A4 inhibitor) at a dose of 200 mg / day resulted in a 1.4- and 2.0-fold increase in C Max and AUC of solifenacin, while the administration of ketoconazole at a dose of 400 mg / day resulted in a 1.5 - and 2.8-fold increase in C Max and AUC of solifenacin.

With simultaneous use of tamsulosin with ketoconazole at a dose of 400 mg / day, a 2.2- and 2.8-fold increase in C Max and tamsulosin AUC were observed, respectively.

With simultaneous use of tamsulosin with cimetidine, a weak CYP3A4 inhibitor (400 mg every 6:00), a 1.44-fold increase in tamsulosin AUC was observed, whereas C Max did not change significantly. The drug Vesomni can be used simultaneously with weak inhibitors of CYP3A4.

The simultaneous use of tamsulosin with paroxetine, a potent inhibitor of CYP2D6 (20 mg per day) resulted in a 1.3 and 1.6 fold increase in C Max and AUC of tamsulosin, respectively. The drug Vesomni can be used simultaneously with CYP2D6 inhibitors.

The effect of induction enzymes on the pharmacokinetic properties of solifenacin and tamsulosin has not been studied. Since solifenacin and tamsulosin is metabolized by CYP3A4, pharmacokinetic interactions with inducers of CYP3A4 (for example rifampicin) are possible, which can reduce the concentration of solifenacin and tamsulosin in the blood plasma.

Other interactions.

Solifenacin.

Solifenacin can reduce the effects of drugs that stimulate the motility of the gastrointestinal tract, such as Metoclopramide and cisapride. In vitro studies of solifenacin have indicated that therapeutic concentrations of solifenacin do not inhibit CYP1A1 / 2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4, therefore no interactions are expected between Solifenacin and drugs that are metabolized with these CYP enzymes . Taking solifenacin does not change the pharmacokinetics of R-warfarin or S-warfarin, or their effect on prothrombin time. Solifenacin has been shown to have virtually no effect on Digoxin pharmacokinetics.

Tamsulosin.

The simultaneous use of tamsulosin with other blockers alpha 1 - adrenergic receptors can lead to hypotensive action. In vitro studies, the amount of tamsulosin free fraction in human plasma did not change with the simultaneous use of drugs such as diazepam, propranolol, trichlormethiazide, chlormadinone, Amitriptyline, Diclofenac, glibenclamide, Simvastatin or Warfarin . Tamsulosin does not change the amount of the free fraction of diazepam, propranolol, trichloromethiazide or chlormadinone. Although diclofenac and warfarin may increase the rate of elimination of tamsulosin. Simultaneous use with Furosemide leads to a decrease in plasma tamsulosin levels, but since tamsulosin levels remain within the therapeutic range, simultaneous use of tamsulosin and furosemide is acceptable. In vitro studies of tamsulosin have shown that at therapeutic concentrations tamsulosin does not virtually suppress CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. Therefore, no interactions are expected between tamsulosin and drugs that are metabolized with the participation of data from CYP enzymes. There are no cases of tamsulosin interaction with simultaneous use with Atenolol, Enalapril or theophylline.

Adult men, including older men.

Take orally 1 tablet of the drug Vesomny (6 mg / 0.4 mg) once a day, regardless of the meal. The maximum daily dose of the drug Vesomni is 1 tablet (6 mg / 0.4 mg). The pills are taken whole, not chewed but not crushed.

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 individual active ingredients of the drug is well studied (see Section “Pharmacokinetic properties”). The drug Vesomny can be prescribed to patients with mild and moderate renal insufficiency (creatinine clearance> 30 ml / min). For patients with severe renal insufficiency (creatinine clearance ≤ 30 ml / min), use the drug with caution and not exceed the maximum daily dose.

Patients with impaired liver function. The effect of hepatic insufficiency on the pharmacokinetics of Vesomney has not been studied. However, the effect on the pharmacokinetics of individual active ingredients of the drug has been well studied (see Section “Pharmacokinetic properties”). Vesomny can be prescribed to patients with mild hepatic insufficiency (Child-Pugh ≤ 7). Patients with moderate hepatic insufficiency (assessment on the Child-Pugh scale 7-9) should use the drug with caution and not exceed the maximum daily dose. For patients with severe liver failure (Child-Pugh rating> 9), the use of the drug Vesomni is contraindicated.

Moderate and potent inhibitors of cytochrome P450 ZA4. Vesomni should be used with caution in patients who are simultaneously treated with moderate or strong CYP3A4 inhibitors (such as Verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole).

Children.

The drug is not intended for use in children (under the age of 18 years).

Overdose

Symptoms Overdose when using a combination of solifenacin and tamsulosin can potentially lead to a severe anticholinergic effect with the development of acute arterial hypotension. The highest doses, taken by chance during clinical trials, were 126 mg of solifenacin succinate and 5.6 mg of tamsulosin hydrochloride. These doses were well tolerated, when administered for 16 days of treatment, moderate dry mouth was reported.

Treatment.

In the case of an overdose of the drug solifenacin and tamsulosin, the patient should take activated charcoal. Gastric lavage may be useful during the first hour after taking the drug, but should not induce vomiting.

Symptoms of solifenacin overdose, like other anticholinergic drugs, can be treated as follows:

• severe anticholinergic effects on the central nervous system, hallucinations or other pronounced disorders: treatment with the use of physostigmine or Carbachol;
• convulsions or severe irritability: treatment with benzodiazepines;
• respiratory failure: treatment with the use of artificial respiration;
• tachycardia symptomatic treatment, if necessary. Beta blockers should be used with caution, since concomitant tamsulosin overdose can potentially cause severe hypotension;
• urinary retention: catheterization.

As with other antimuscarinic drugs, in case of overdose, special attention should be given to patients with an established risk of developing a prolongation of the QT interval (for example, with hypokalemia, bradycardia, and simultaneous use of drugs that can prolong the QT interval) and corresponding to pre-existing heart diseases ( eg myocardial ischemia, arrhythmia, heart failure).

Acute hypotension, which is possible with an overdose of tamsulosin, should be treated symptomatically. Since tamsulosin binds to plasma proteins very well, hemodialysis is unlikely.

Special instructions

Other causes of frequent urination (heart failure or kidney disease) should be assessed before taking Vesomni.
If urinary tract infection is present, appropriate antibiotic therapy should be initiated.
Anaphylactic reaction was noted in some patients who received treatment with solifenacin after registering the drug. With the development of Anaphylactic reactions, Vesomnia treatment should be discontinued and should not be resumed.
As with other α1-adrenergic blockers, with tamsulosin treatment, in some cases, a decrease in blood pressure can be observed, which in rare cases can lead to fainting. Patients beginning to take Vesomny should be warned of the need to sit or lie down at the first sign of orthostatic hypotension (dizziness, weakness) or remain lying down until the signs disappear.
In some patients taking or previously taking tamsulosin hydrochloride, during surgery for cataract and glaucoma, the syndrome of intraoperative instability of the iris of the eye (narrow pupil syndrome) was observed, which can lead to complications during surgery or in the postoperative period. It is not recommended to start Vesomni therapy in patients who are scheduled for cataract or glaucoma surgery. The feasibility of discontinuing Vesomni therapy for 1-2 weeks before surgery for cataracts or glaucoma has not yet been proven. During the preoperative examination of patients, the surgeon and the ophthalmologist should consider whether this patient is accepting or accepting Vesomni. This is necessary to prepare for the development of the syndrome of intraoperative instability of the iris.
Vesomni should be used with caution in combination with strong and moderate CYP3A4 inhibitors, for example, verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole. Prepa