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Active ingredients
Silodozin
Release form
Capsules
Composition
In 1 caps. Silodosin 4 mg is contained. Adjuvants: mannitol - 132.4 mg, pregelatinized starch (1500 starch) - 9 mg, pregelatinized starch (PCS PC-10 starch) - 26 mg, sodium lauryl sulfate - 1.8 mg, magnesium stearate - 1.8 mg.
Pharmacological effect
Silodosin is a highly selective drug, an α1A-adrenoreceptor antagonist, contained mainly in the prostate gland, at the bottom of the bladder, in the bladder neck, in the prostate capsule and in the prostate urethra. The blockade of α1A-adrenoreceptor data provides relaxation of the smooth muscles of this section, which, in turn, increases the rate of urine outflow without affecting the contractility of the smooth muscle of the detrusor. As a result, the symptoms of irritation and obstruction due to benign prostatic hyperplasia (BPH) disappear. Sylodosin is characterized by much lower affinity for α1B-adrenoreceptors, which are localized mainly in the tissues of the cardiovascular system. α1B correlates as 162: 1. It is well known that the improvement of symptoms on the scale of the American Urological Association (AUA) is provided when taking silodozin 4 mg or 8 mg significantly better than with placebo. Clinical studies conducted in the United States and Europe with silodosin at a dose of 8 mg 1 time per day demonstrated a significant decrease in the symptoms of BPH, both accumulation (irritation) and release (obstruction) compared with placebo, according to the International Scale for Prostatic Symptoms ( International Prostate Symptom Score (IPSS) after 12 weeks of treatment. During clinical studies conducted in Europe, silodosin at a dose of 8 mg 1 time per day was no less effective for tamsulosin at a dose of 0.4 mg 1 time per day. The incidence of a positive response to treatment, that is, an improvement in overall IPSS score, was significantly higher in the silodosin and tamsulosin group compared with placebo. In the long-term, open, extended phase of these clinical studies in which patients received silodosin up to 1 year, symptoms improved under the influence of silodosin, the 12th week of treatment was maintained for more than 1 year. In the fourth phase of a clinical study that was conducted in Europe according to the evaluation of the International Scale for Prostatic Symptoms, 77.1% of patients had treatment review.In about half of the cases, patients with the most annoying symptom, namely, nocturia, increased urination, weakened flow, urge to urinate, urine leaks at the end of urination, and incomplete emptying of the bladder, reported an improvement in condition as indicated in the International Organization questionnaire on problems of urinary incontinence (International Continence Society, ICS) for men. In all clinical studies, conducted under the condition of receiving silodosin, there was no significant decrease in arterial pressure of the patient in a horizontal position
Pharmacokinetics
The pharmacokinetic characteristics of silodosin and its major metabolites were evaluated when the drug was taken by adult male patients, healthy or sick BPH, after a single and / or multiple dose in doses from 0.1 mg to 48 mg per day. In the indicated dose range, the pharmacokinetic characteristics of silodosin vary linearly. The exposure of the main metabolite, silodosin glucuronide (KMD-3213G), in plasma in the equilibrium state is 3 times the original drug. Silodosin and its glucuronide reach a state of equilibrium after 3 days and 5 days of treatment, respectively. AbsorptionSilodosin when administered orally is well absorbed by the body, the absorption value is proportional to the dose administered. Absolute bioavailability of the drug is about 32%. In vitro studies with Caco-2 cells showed that silodosin is a substrate of P-glycoprotein. In the case of taking the drug with food, the value of Cmax decreases by about 30%, tmax increases by about 1:00, the change in value AUC is not observed. After taking 8 mg once a day immediately after breakfast for 7 days, the following pharmacokinetic indicators were determined: Сmax - 87 ± 51 ng / ml (cb), tmax - 2.5 hours (range 1.0-3, 0), AUC - 433 ± 286 ng / h / ml. Distribution The volume distribution of silodosin is 0.81 l / kg. Silodosin is 96.6% bound to plasma proteins. It is not distributed in the blood cells. Gluuronide is 91% bound to silodosin proteins. Biological transformation Silodosin metabolism occurs through glucuronization (UGT2B7), alcohol and aldehyde dehydrogenase, and oxidation, mainly CYP3A4. The main plasma metabolite, conjugated silodosin glucuronide (KMD-3213G), whose activity is confirmed in vitro, is characterized by a longer half-life (approximately 24 hours), its concentration in plasma is approximately 4 times higher than the concentration of silodosin itself.In vitro data indicate that silodosin does not inhibit or potentiate the isoenzymes of the cytochrome P450 system. Conclusion After taking silodosin, after 7 days, approximately 33.5% is excreted in the urine and 54.9% in feces. Total silodosin clearance is approximately 0.28 l / h / kg. Silodosin is excreted mainly in the form of metabolites, and only an extremely small percentage of the drug is excreted unchanged in the urine. The terminal half-life of an unchanged drug and its glucuronides is approximately 11:00 and 18 hours, respectively. Pharmacokinetics in special groups of patientsPatients of elderly age The characteristics of exposure to silodosin and its main metabolites do not depend on the age of the patient. The total clearance of silodosin remains unchanged in the case of patients taking over 75 years of age. Liver function impairment The pharmacokinetic characteristics of silodosin are the same in patients with moderate liver function impairment (Child-Pugh score is 7–9 points) and in healthy volunteers. The results of this study should be interpreted with caution, since the patients had normal biochemical indices indicating normal metabolic function, and they were classified as patients with moderate hepatic impairment, taking into account ascites and hepatic encephalopathy. The pharmacokinetics of silodosin in patients with severely impaired liver function has not been studied. Renal dysfunction A study of the results of a single dose showed that Cmax and AUC of silodosin (unbound) when receiving patients with impaired renal function with moderate or moderate severity rises to 1.6 and 1 , 7 times, respectively, compared with rates in patients with normally functioning kidneys. In patients with severe impaired renal function, Cmax increased by 2.2 times and AUC - by 3.7 times. The value of the pharmacokinetic characteristics of the main metabolites of the drug, silodosin glucuronide and KMD3293 also increased. The concentration of silodosin in the blood plasma after 4 weeks of taking patients with impaired renal function of moderate severity is the same as in patients with normally functioning kidneys,and in patients with moderately severe renal dysfunction, the concentration doubles. A review of all the safety data of the drug suggests that silodosin therapy for moderately severe renal dysfunction is not associated with an increased risk of dizziness or orthostatic hypotension compared with therapy in patients with normally functioning kidneys. So, dose adjustment for patients with moderately severe renal impairment is not required. Due to the limited data on the results of taking the drug by patients with impaired renal function of moderate severity, the initial recommended dose of the drug is 4 mg. The use of silodosin in the treatment of patients with severe renal impairment is not recommended
Indications
Symptomatic treatment of benign prostatic hyperplasia (BPH).
Contraindications
Hypersensitivity to the active substance or any of the auxiliary components or their intolerance Children under 18 Severe renal failure (creatinine clearance less than 30 ml / min) Severe hepatic insufficiency (not enough clinical data) With caution: with mild and moderate renal failure (creatinine clearance from 30 to 50 ml / min).
Precautionary measures
As with other adrenergic blockers, a decrease in blood pressure or orthostatic hypotension may be observed during treatment with silodosin.
Use during pregnancy and lactation
Contraindicated
Dosage and administration
Adults. Apply inside. The recommended dose is 8 mg 1 time per day. For individual groups of patients, 1 capsule of Urorec 4 mg 1 time per day is recommended. The drug should be taken with food, preferably at the same time of the day. The capsule does not need to be broken, it should be swallowed whole, without chewing, with a glass of water. Elderly patients Dose adjustment for elderly patients is not required. Patients with impaired renal functionDose adjustment for patients with moderately impaired renal function (CLRR from ≥50 to <80 ml / min) is not required. In the case of moderate renal dysfunction (CLR from ≥30 to <50 ml / min), start therapy with a dose of 4 mg of silodosin 1 time per day, after which, taking into account the individual reaction of the body, after 1 week of treatment, the dose can be increased to 8 mg 1 time per day.The use of the drug in the treatment of patients with severe impaired renal function (CLCR <30 ml / min) is not recommended. Patients with impaired liver function. Dose adjustment for patients with moderate or moderate severity of impaired liver function is not required. Since there is no clinical experience of using the drug in the treatment of patients with severe liver dysfunction, the administration of a drug to this category of patients is not recommended.
Side effects
Ejaculation disorders, such as retrograde ejaculation and anejaculation (decrease or absence of ejaculation), with a frequency of 23% were frequent undesirable reactions that were reported during therapy with silodosin during placebo-controlled clinical studies and during long-term use. This may temporarily affect the reproductive ability of a man. And she recovers a few days after stopping treatment.
Overdose
Silodozin was evaluated in doses up to 48 mg / day, which were taken by healthy human volunteers. An orthostatic hypotension was the dosage-limiting adverse reaction. If the drug was recently taken, it is recommended to induce vomiting in the patient or to wash the stomach with it. If overdose of Urorec is accompanied by hypotension, it is necessary to provide the patient with support for the work of the cardiovascular system. Dialysis is impractical because silodosin in the body is almost completely bound to blood proteins (96.6%).
Interaction with other drugs
Silodosin is extensively metabolized, especially by CYP3A4, alcohol dehydrogenase, and UGT2B7. Silodosin also acts as a substrate for P-glycoprotein. Substances that inhibit or induce these enzymes and transporters can affect plasma concentrations of silodosin and its active metabolites α-blockers. There is no adequate information about the safety of silodosin in simultaneous therapy with α-adrenoreceptor antagonists. In this regard, simultaneous use of α-adrenoreceptors with other antagonists is not recommended. Inhibitors of isoenzymes of the CYPRZA system According to a study of drug interactions, it was found that when used simultaneously with inhibitors of isoenzymes of the system of CYPRA4 (ketoconazole, 400 mg), the maximum concentration of silodosin in the blood increases in 3, 7 times, and the effect of silodosin (AUC value) increases 3.1 times.Simultaneous use with inhibitors of isoenzymes of the system of CYPRA4 (such as ketoconazole, itraconazole or ritonavir) is not recommended. With simultaneous use of silodosin with moderate inhibitors of the isoenzymes of the system of CYPRA4, such as diltiazem, an increase in the AUC value of about 30% was observed, but Сmax value and the half-life remained unchanged. This change has no clinical significance, therefore, dose adjustment is not required. Type 5 phosphodiesterase inhibitors (РDE-5) With simultaneous use of sildenafil at a dose of 100 mg of tadalafil at a dose of 20 mg, there was a minimal pharmacodynamic interaction that did not cause a clinically significant significant decrease in systolic or diastolic blood pressure according to the results of the orthostatic test (in a vertical position against the horizontal position). In patients over 65, the mean decrease at different times was between 5 and 15 mmHg. (systolic) and 0 and 10 mm Hg. (diastolic). With simultaneous use of drugs, positive orthostatic tests were not much more often; however, there were no cases of symptomatic orthostatic hypotension or dizziness. Patients taking the Urorec drug simultaneously with PDE-5 inhibitors should be monitored to avoid possible adverse reactions. Antihypertensive drugs In a clinical study program, many patients received simultaneous antihypertensive therapy (mainly substances affecting the renin-angiotensin system, beta-blockers, antagonists calcium and diuretics) without increasing the likelihood of orthostatic hypotension. However, care should be taken when starting to take antihypertensive drugs at the same time; It is necessary to monitor patients for possible side effects. Digoxin When administered simultaneously with silodosin at a dose of 8 mg 1 time per day, the concentration of digoxin, the substrate of P-glycoprotein, changed slightly in equilibrium. No dose adjustment required
special instructions
Intraoperative Flabby Iris SyndromeInteroperative flabby iris syndrome (a variant of the sluggish reaction of the pupil) was observed during surgery for cataracts in some patients who take α1-blockers or have taken them before.Such a complication may increase the risk of procedural complications during the operation. Patients are not recommended to start treatment with Urorec before a planned cataract surgery. It is recommended that therapy be discontinued using α1-blockers 1-2 weeks before cataract surgery, but the duration of cessation of therapy in surgery due to cataracts and the benefits of this have not yet been established. During preparation for surgery for cataract, surgeons and ophthalmologists should find out whether the patient is taking or has previously taken the drug Urorec, in order to take appropriate measures to prevent the intraoperative syndrome of flabby iris during surgery. Ortho aticheskie yavleniyaOrtostaticheskie phenomenon during Urorec treatment are very rare. However, in some patients, a decrease in blood pressure is possible, in some cases, it can lead to loss of consciousness. At the first signs of orthostatic hypotension (for example, in the case of orthostatic dizziness), the patient should be placed or put on until the symptoms disappear. Patients suffering from orthostatic hypotension, therapy with Urorec is not recommended. Disruption of renal function. Use of Urorec for treatment of patients with severely impaired renal function (СL С R <30 ml / min) is not recommended. Disruption of liver function. liver is not recommended because there is no necessary information. Prostate carcinoma. Due to the fact that BPH and carcinoma of the prostate are accompanied by the same symptoms, and both of these diseases can occur At the same time, and before prescribing the patient the treatment of Urorec in connection with BPH, prostate carcinoma should be excluded. It should be a digital rectal examination. Also, if necessary, a prostate-specific antigen (PSA) should be determined prior to treatment and at regular intervals after it. Reproductive ability Treatment with Urorec will limit ejaculation during orgasm and may temporarily affect the male reproductive ability.Cases of retrograde ejaculation (orgasm with limited or without ejaculation) have been reported in patients taking silodozin. This effect disappears after discontinuation of the drug Urorec. Before initiating therapy, the patient should be informed about the possibility of retrograde ejaculation. Ability to influence the reaction rate when driving or other mechanisms. Specialized studies to determine the effect of the drug on driving ability, other equipment were not performed. Patients should be warned about the possibility of occurrence of orthostatic hypotension events (such as dizziness), and also warn against driving a car or other equipment before they learn how Urorec affects their condition.