Vesomni®

Brand Astellas

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Clinical Pharmacology

The drug Vesonne is a combination drug containing two active ingredients, solifenacin and tamsulosin. These active ingredients have independent and complementary mechanisms of action for the treatment of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH), in the presence of symptoms of bladder filling.

Solifenacin is a selective competitive antagonist of muscarinic receptors, does not have affinity for other receptors, enzymes or ion channels. Solifenacin has a high affinity for muscarinic M 3 receptors, and less affinity for muscarinic M 1 and M 2 receptors.

Tamsulosin is an alpha 1 -adrenoreceptor blocker. Tamsulosin binds selectively and competitively to postsynaptic alpha 1 -adrenoreceptors, especially the alpha 1 A and alpha 1D subtypes, which are responsible for relaxing the smooth muscles of the lower urinary tract.

Solifenacin relieves bladder filling symptoms (irritative symptoms) associated with the action of acetylcholine, which activates M 3 cholinergic receptors in the bladder. Acetylcholine activates the contractile function of the bladder wall, manifested as an urgent urge to urinate or urinary incontinence.

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

Pharmacokinetics.

A bioavailability study with repeated administration showed that the pharmacokinetics when taking Vesomni is compared with the pharmacokinetics while taking solifenacin and tamsulosin.

Suction

After repeated administration of Vesomni, the time to reach the maximum concentration of T Max for solifenacin varies between 4.27 and 4.76 hours in various studies, for tamsulosin between 3.47 and 5.65 hours, respectively. The maximum plasma concentration (C Max) 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 for solifenacin ranged from 528 ng / h / ml to 601 ng / h / ml, and tamsulosin ranged from 97.1 ng / h / ml and 222 ng / h / ml. The bioavailability of solifenacin was about 90%, while tamsulosin is absorbed by 70% - 79% of the dose applied.

A study was conducted of Vesomni medication when a single dose was applied simultaneously with a meal, during a low-fat meal, with a low-calorie breakfast, and with a high-fat meal and a high-calorie meal. After a high-fat meal, a high-calorie breakfast, there was an increase in C max for tamsulosin by 54% compared with an empty stomach drug, in which the AUC increased by 33%. The pharmacokinetics of solifenacin do not change with a low-fat meal, with a low-fat breakfast, or with a high-fat meal or a high-calorie meal.

The simultaneous use of solifenacin and tamsulosin OCAS leads to an increase in C max by 1.19 times and an increase in the AUC of tamsulosin by 1.24 times compared to the AUC of tamsulosin OCAS in monotherapy. There are no indicators of the effect of tamsulosin on the pharmacokinetics of solifenacin.

Conclusion.

After a single dose of Vesomni, the half-life of t 1/2 of solifenacin ranged from 49.5 hours to 53 hours; tamsulosin - from 12.8 hours to 14 hours.

Repeated use of verapamil in a dose of 240 mg simultaneously with the Vesomni drug leads to an increase in solifenacin - C max by 60% and AUC by 63%, while for tamsulosin C max increases to 115% and AUC - to 122%. Changes in C max and AUC are not clinically significant.

Analysis of the pharmacokinetic data during phase 3 clinical trials shows the variability of the pharmacokinetics of tamsulosin, depending on age, height and blood concentration α 1 - acid glycoprotein. An increase in AUC is associated with an increase in α 1 - an acidic glycoprotein and age, while a decrease in AUC is associated with a decrease in growth. In addition, an increase in gamma-glutamyl transferase is associated with high AUC values. These changes in AUC values are not clinically significant.

Information on the pharmacokinetics of the active ingredients of the combined drug complements the pharmacokinetic properties of the drug Vesomni.

Solifenacin.

Suction

The time to reach the maximum concentration of T Max does not depend on the dose and ranges from 3 to 8:00 after taking several doses. The value of C Max and AUC increase in proportion to the dose from 5 to 40 mg. Bioavailability is approximately 90%.

Distribution. The volume of distribution of solifenacin after administration of the drug is about 600 liters. Approximately 98% of solifenacin is bound to plasma proteins, primarily with the α 1 -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 CYP3A4. However, there are alternative metabolic pathways that can affect the metabolism of solifenacin. The solifenacin system clearance 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 solifenacin) were determined (except for solifenacin).

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

Tamsulosin.

Suction For tamsulosin in the form of OCAS, T Max is in the range from 4 to 6:00 after several doses of 0.4 mg / day. C Max and AUC increase in proportion to the dose of 0.4 to 1.2 mg. Absolute bioavailability of 57%.

Distribution. The volume of distribution of tamsulosin after administration is about 16 liters. Approximately 99% of tamsulosin binds to plasma proteins, primarily with the α 1 -acid glycoprotein.

Metabolism. Tamsulosin has a low first-pass effect, it is slowly metabolized. Tamsulosin is extensively metabolized in the liver, mainly with CYP3A4 and CYP2D6. The systemic clearance of tamsulosin is about 2.9 l / h. Most of the tamsulosin used is present in plasma as the unchanged active substance. None of the metabolites was more active than the original substance.Conclusion. In the case of a single dose of 0.2 mg of 14 C-labeled tamsulosin, after 1 week of treatment, about 76% of the radioactivity is excreted in the urine and 21% in the feces. In the urine about 9% of radioactivity was found unchanged as tamsulosin, about 16% as sulphate on diethyl tamsulosin, and 8% as etoxyfenoxyl acetic acid.

Characteristics in special patient groups.

Elderly patients.

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

Renal failure.

The drug Vesomni is used in patients with mild to moderate renal insufficiency, but caution should be exercised when used in patients with severe renal insufficiency.

The pharmacokinetics of the drug Vesomny has not been studied in patients with renal insufficiency.

The following data reflects information about 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 differ slightly from the corresponding indicators in healthy volunteers. In patients with severe renal insufficiency (creatinine clearance ≤ 30 ml / min), the exposure of solifenacin is much higher - the increase in C Max is about 30%, the AUC is more than 100% and the t 1/2 is 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 renal failure (30≥ creatinine clearance

Liver failure.

The drug Vesomny is used in patients with moderate to moderate hepatic insufficiency, but is contraindicated in patients with severe hepatic insufficiency.

The pharmacokinetics of the drug Vesomny has not been studied in patients with hepatic insufficiency.

The following data reflects information about liver failure characteristic of each of the active ingredients of the drug.

Solifenacin.

In patients with moderate hepatic impairment (7–9 points on the Child-Pue scale), the CMax value does not change, the AUC increases by 60%, and t 1/2 is doubled.

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

Tamsulosin.

The pharmacokinetics of tamsulosin were compared in 8 patients with moderate hepatic insufficiency (7–9 on the Child-Pugh scale) and in 8 healthy patients. Changes in the total concentration of tamsulosin in the blood plasma due to changes in the connection with α 1 -oxidized glycoprotein, the active concentration of tamsulosin hydrochloride was markedly unchanged, and the internal clearance of inactive tamsulosin was moderate (32%). The pharmacokinetics of tamsulosin in patients with severe hepatic insufficiency has not been studied.

Indications

Treatment of symptoms of bladder filling (imperative urination, frequent urination) of moderate and severe, and symptoms of bladder emptying (obstructive symptoms) associated with benign prostatic hyperplasia (BPH) in men who do not have monotherapy.

Composition

1 tablet contains:

Active substances: 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.

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Dosage and Administration

Adult men, including older men.

To Administered orally on 1 tablet of a medicine of Vesomni (6 mg / 0,4 mg) once a day irrespective of 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 failure on the pharmacokinetics of Vesomney has not been studied. However, the effect on the pharmacokinetics of individual active ingredients of the drug is well studied (see Section “Pharmacokinetic properties”). Vesomny can be prescribed to patients with mild hepatic insufficiency (Child-Pugh ≤ 7). Patients with moderate hepatic impairment (Child-Pugh score 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).

Adverse reactions

Vesomnia can cause side effects associated with the m-anticholinergic action of solifenacin, usually with 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 studies.
In the table below, the column "The frequency of adverse reactions when taking Vesomni" reflects the adverse reactions recorded during a 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 Vesomni .
The frequency of adverse reactions is determined as follows: very often (≥1 / 10); often (≥1 / 100 to * were observed after registration of the drug. Due to the fact that the data were obtained by the method of spontaneous messages in the period after registration, determining the frequency and causal relationship with taking tamsulosin and solifenacin is difficult.
Vesomny 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.

Contraindications

Hypersensitivity to the active substances or to any of the excipients. Hemodialysis. Severe liver failure. Severe renal failure, which use powerful inhibitors of cytochrome P450 (CYP) 3A4, such as ketoconazole. Mild liver dysfunction, which also use powerful inhibitors of CYP3A4, such as ketoconazole.

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

Drug interactions

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 taking 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 with CYP3A4, pharmacokinetic interactions with CYP3A4 inducers (for example, rifampicin) are possible, which can reduce plasma plasma concentration of solifenacin and tamsulosin.

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 indicated that solifenacin at therapeutic concentrations does 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 blood plasma did not change with the simultaneous use of such drugs as diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin or warfarin. Tamsulosin does not change the amount of diazepam, propranolol, trichloromethiazide or chlormadinone free fraction. Although diclofenac and warfarin may increase the rate of elimination of tamsulosin. Simultaneous use with furosemide leads to a decrease in plasma tamsulosin, but since the level of tamsulosin remains within the therapeutic range, the 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.

Special instructions

Other causes of frequent urination (heart failure or kidney disease) should be assessed before taking Vesomne.
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 renewed.
As with other α1-adrenergic blockers, with tamsulosin treatment, in some cases, a decrease in blood pressure may be observed, which in rare cases may 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 symptoms 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 expediency of discontinuing Vesomnia therapy 1-2 weeks before cataract or glaucoma surgery 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. The drug should not be used in patients with metabolic imbalance of CYP2D6 isoenzyme in combination with strong inhibitors of CYP3A4 or strong inhibitors of CYP2D6, for example, paroxetine.
Patients with renal failure:
Vesomny can be used in patients with mild and moderate renal insufficiency (CC> 30 ml / min), but should be used with caution in patients with severe renal insufficiency (CC = 30 ml / min), for which the maximum daily dose is one tablet of Vesomne (6 mg (0.4 mg).
Patients with liver failure:
Vesomni can be used by patients with mild hepatic impairment (Child-Pugh score ≤ 7). Patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale) should take the drug with caution (the maximum daily dose is one tablet of Vesomni (6 mg / 0.4 mg)). Patients with severe hepatic insufficiency (score on the Child-Pugh scale above 9) use Vesomni contraindicated.
Pregnancy and lactation:
Vesomni drug is used only in men.
Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous machinery:
Studies on the effects of Vesomni on the ability to drive and engage in potentially hazardous activities have not been conducted. However, the patient should be informed about the possible occurrence of dizziness, blurred vision, fatigue and less sleepiness, which can adversely affect the ability to drive and work with mechanisms.

Overdosage

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 case of overdosing 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 marked disorders: treatment with 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 the event of an 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 the simultaneous use of drugs that can prolong the QT interval) and the corresponding 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.