Arilozin hard capsules 4 mg blister No. 30

Instructions for use Arilozin hard capsules 4 mg blister No. 30

Composition

active ingredient: silodosin;

1 capsule contains 4 mg or 8 mg of silodosin;

excipients: mannitol, pregelatinized corn starch, sodium lauryl sulfate, glycerol dibehenate;

capsule shell: gelatin, titanium dioxide (E 171), black printing ink (shellac (bleached, washed), propylene glycol, concentrated ammonium solution, iron (II,III) oxide (E172), potassium hydroxide), for a dosage of 4 mg - iron (III) hydroxide-oxide (E172).

Dosage form

The capsules are hard.

Main physicochemical properties:

4 mg - yellow, opaque, hard gelatin capsule, size 3, with the inscription "4" printed in black ink on the cap;

8 mg - white, opaque, hard gelatin capsule, size 0, with "8" printed in black ink on the cap.

Pharmacotherapeutic group

α-Adrenoceptor antagonists. Silodosin.

ATX code G04C A04.

Pharmacological properties

Pharmacodynamics

Silodosin is a highly selective α1A-adrenergic receptor antagonist, which is found mainly in the prostate gland, at the bottom of the bladder, in the bladder neck, in the prostate capsule and the prostatic part of the urethra. Blockade of α1A-adrenergic receptors provides relaxation of the smooth muscles of this department, which, in turn, increases the rate of urine outflow without affecting the contractility of the detrusor smooth muscle. As a result, the symptoms of irritation and obstruction caused by benign prostatic hyperplasia (BPH) disappear.

Silodosin has a much lower affinity for α1B-adrenoceptors, which are localized mainly in the tissues of the cardiovascular system.

In vitro studies have shown that silodosin binds to α1A and α1B adrenoceptors in a ratio of 162:1.

It is well established that improvement in American Urological Association (AUA) symptom scores is significantly greater with silodosin 4 mg or 8 mg than with placebo. Clinical trials conducted in the United States and Europe with silodosin 8 mg once daily have demonstrated significant improvements in both storage (irritation) and discharge (obstruction) symptoms of BPH compared with placebo, as measured by the International Prostate Symptom Score (IPSS), after 12 weeks of treatment. In clinical trials conducted in Europe, silodosin 8 mg once daily was non-inferior to tamsulosin 0.4 mg once daily. The response rate, i.e. improvement in the overall IPSS score, was significantly higher in the silodosin and tamsulosin groups compared with placebo.

In the long-term open-label extension phase of these clinical trials, in which patients received silodosin for up to 1 year, the improvement in symptoms with silodosin at week 12 of treatment was maintained for more than 1 year.

In a phase IV clinical trial conducted in Europe, 77.1% of patients responded to treatment according to the International Prostatic Symptom Score. Approximately half of patients with the most bothersome symptoms—nocturia, increased urinary frequency, weak stream, urgency, dribbling at the end of urination, and incomplete bladder emptying—reported improvement as measured by the International Continence Society (ICS) Male Incontinence Questionnaire.

In all clinical studies conducted with silodosin, no significant decrease in supine blood pressure was observed.

Silodosin at doses of 8 mg and 24 mg per day compared to placebo had no statistically significant effect on ECG intervals or cardiac repolarization.

Pharmacokinetics

The pharmacokinetics of silodosin and its major metabolites have been evaluated in adult male patients, healthy or with BPH, after single and/or multiple doses of 0.1 mg to 48 mg/day. The pharmacokinetics of silodosin are linear over this dose range.

The plasma exposure of the major metabolite, silodosin glucuronide (KMD-3213G), at steady state is 3-fold greater than that of the parent drug. Silodosin and its glucuronide reach steady state after 3 days and 5 days of treatment, respectively.

Absorption

Silodosin is well absorbed after oral administration, with absorption being proportional to the administered dose. The absolute bioavailability of the drug is approximately 32%.

An in vitro study with Caco-2 cells showed that silodosin is a substrate for P-glycoprotein.

When the drug is taken with food, the Cmax value decreases by approximately 30%, tmax increases by approximately 1 hour, and no change in AUC is observed. After oral administration of 8 mg of the drug once daily immediately after breakfast for 7 days, the following pharmacokinetic parameters were determined: Cmax — 87 ± 51 ng/ml (SD), tmax — 2.5 hours (range 1.0–3.0), AUC — 433 ± 286 ng/h/ml.

Distribution

The volume of distribution of silodosin is 0.81 l/kg. Silodosin is 96.6% bound to plasma proteins. It does not distribute into blood cells.

Protein binding of silodosin glucuronide is 91%.

Silodosin is metabolized by glucuronidation (UGT2B7), alcohol and aldehyde dehydrogenase, and oxidation, mainly by CYP3A4. The main metabolite in plasma, the conjugated glucuronide of silodosin (KMD-3213G), which has been shown to be active in vitro, has a longer half-life (approximately 24 hours) and plasma concentrations are approximately 4 times higher than those of silodosin itself. In vitro data indicate that silodosin does not inhibit or potentiate cytochrome P450 isoenzymes.

Breeding

After oral administration of silodosin, approximately 33.5% is excreted in the urine and 54.9% in the feces after 7 days. The total clearance of silodosin is approximately 0.28 l/h/kg. Silodosin is excreted primarily as metabolites, with only a very small percentage of the drug excreted unchanged in the urine. The terminal half-lives of the unchanged drug and its glucuronides are approximately 11 hours and 18 hours, respectively.

Pharmacokinetics in special patient groups

Elderly patients. The exposure profile of silodosin and its major metabolites is independent of patient age. The total clearance of silodosin remains unchanged in patients over 75 years of age.

Children: The effects of silodosin have not been evaluated in patients under 18 years of age.

Hepatic impairment. The pharmacokinetics of silodosin were similar in patients with moderate hepatic impairment (Child-Pugh score 7-9) and in healthy volunteers. The results of this study should be interpreted with caution because the patients had normal biochemical parameters, indicating normal metabolic function, and were classified as patients with moderate hepatic impairment due to ascites and hepatic encephalopathy. The pharmacokinetics of silodosin in patients with severe hepatic impairment have not been studied.

Renal impairment. A single-dose study showed that Cmax and AUC of silodosin (unbound) were increased 1.6-fold and 1.7-fold, respectively, in patients with mild to moderate renal impairment compared to patients with normal renal function. In patients with severe renal impairment, Cmax was increased 2.2-fold and AUC was increased 3.7-fold. The pharmacokinetics of the major metabolites, silodosin glucuronide and KMD3293, were also increased.

The concentration of silodosin in the blood plasma after 4 weeks of administration in patients with mild renal impairment is the same as in patients with normal renal function, and in patients with moderate renal impairment, the concentration of the drug increases by twofold.

A review of all safety data suggests that silodosin therapy in patients with mild renal impairment is not associated with an increased risk of dizziness or orthostatic hypotension compared to patients with normal renal function. Therefore, no dose adjustment is required in patients with mild renal impairment. Due to limited data in patients with moderate renal impairment, the recommended starting dose is 4 mg. Silodosin is not recommended for use in patients with severe renal impairment.

Indication

For the symptomatic treatment of benign prostatic hyperplasia (BPH).

Contraindication

Hypersensitivity to silodosin or any of the excipients in the medicinal product.

Interaction with other medicinal products and other types of interactions

Silodosin is extensively metabolized, particularly by CYP3A4, alcohol dehydrogenase, and UGT2B7. Silodosin is also a substrate for P-glycoprotein. Substances that inhibit or induce these enzymes and transporters may affect the plasma concentrations of silodosin and its active metabolites.

Alpha blockers

There is no adequate information on the safety of silodosin in concomitant therapy with α-adrenergic receptor antagonists. Therefore, concomitant use with other α-adrenergic receptor antagonists is not recommended (see section 4.4).

Inhibitors of CYP3A4 isoenzymes

A drug interaction study found that when co-administered with a potent CYP3A4 inhibitor (ketoconazole, 400 mg), the maximum plasma concentration of silodosin increased by 3.7-fold and the exposure to silodosin (AUC value) increased by 3.1-fold. Co-administration with potent CYP3A4 inhibitors (such as ketoconazole, itraconazole or ritonavir) is not recommended.

When silodosin was co-administered with moderate inhibitors of CYP3A4, such as diltiazem, an increase in AUC of approximately 30% was observed, but Cmax and half-life remained unchanged. This change is not clinically significant and therefore no dose adjustment is required.

When sildenafil 100 mg or tadalafil 20 mg were co-administered, there was minimal pharmacodynamic interaction, with no clinically significant reduction in systolic or diastolic blood pressure as measured by the orthostatic test (vertical versus supine). In patients over 65 years of age, mean reductions at different time points were between 5 and 15 mmHg (systolic) and 0 and 10 mmHg (diastolic). Positive orthostatic tests were not significantly more frequent during co-administration; however, there were no cases of symptomatic orthostatic hypotension or dizziness. Patients receiving silodosin concomitantly with PDE-5 inhibitors should be monitored for possible adverse reactions.

Antihypertensive drugs

In the clinical trial program, many patients received concomitant antihypertensive therapy (mostly agents acting on the renin-angiotensin system, beta-blockers, calcium antagonists, and diuretics) without an increased risk of orthostatic hypotension. However, caution should be exercised when initiating concomitant antihypertensive therapy; patients should be monitored for adverse events.

Digoxin

When co-administered with silodosin 8 mg once daily, the steady-state concentration of digoxin, a P-glycoprotein substrate, was not significantly altered. No dose adjustment is required.

Application features

Intraoperative floppy iris syndrome

Intraoperative floppy iris syndrome (a variant of sluggish pupillary response syndrome) has been observed during cataract surgery in some patients receiving or previously receiving α1-blockers. This complication increases the risk of procedural complications during surgery.

Patients are not recommended to start silodosin treatment before elective cataract surgery. Discontinuation of α1-blocker therapy 1–2 weeks before cataract surgery is recommended, but the duration of discontinuation prior to cataract surgery and the benefits of this have not yet been established.

When preparing for cataract surgery, surgeons and ophthalmologists should inquire whether the patient is taking or has previously taken silodosin, in order to take appropriate measures to avoid intraoperative floppy iris syndrome during surgery.

Orthostatic phenomena

Orthostatic phenomena during treatment with silodosin occur very rarely. However, in some patients, a decrease in blood pressure may occur, which in some cases 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 seated or lying down until the symptoms disappear. Silodosin therapy is not recommended for patients suffering from orthostatic hypotension.

Kidney dysfunction

Use of silodosin in the treatment of patients with severe renal impairment (CK [creatinine clearance]

Liver dysfunction

The use of silodosin in patients with severe hepatic impairment is not recommended due to lack of sufficient information.

Prostate carcinoma

Since BPH and prostate carcinoma have similar symptoms and can occur simultaneously, prostate carcinoma should be excluded before initiating treatment with silodosin for BPH. A digital rectal examination should be performed. Prostate-specific antigen (PSA) should also be measured before starting treatment and regularly thereafter, if necessary.

Reproductive ability

Treatment with silodosin results in reduced ejaculation during orgasm and may temporarily affect male fertility. Retrograde ejaculation (orgasm with reduced or no ejaculation) has been reported in patients taking silodosin. This effect resolves after discontinuation of the drug.

Before starting therapy, the patient should be informed about the possibility of retrograde ejaculation.

The medicinal product contains the excipient glycerol dibehenate, which may cause headache, gastrointestinal irritation and diarrhoea. Mannitol may have a mild laxative effect.

Use during pregnancy or breastfeeding

Silodosin is intended for the treatment of male patients only.

Ability to influence reaction speed when driving vehicles or other mechanisms

No specific studies have been conducted to determine the effect of the drug on the ability to drive or use machines. Patients should be warned about the possibility of orthostatic hypotension (such as dizziness) and advised not to drive or use machines until they know how silodosin affects them.

Method of administration and doses

For adults. Take orally. The recommended dose is 8 mg once daily. For certain patient groups, 1 capsule of silodosin 4 mg once daily is recommended (see below).

The medicine should be taken with food, preferably at the same time of day. The capsule should not be broken - it should be swallowed whole, without chewing, with a glass of water.

Elderly patients: No dose adjustment is required for elderly patients (see section 5.2).

Patients with renal impairment. No dose adjustment is required for patients with mild renal impairment (creatinine clearance ≥ 50 to 80 ml/min). In case of moderate renal impairment (creatinine clearance ≥ 30 to 50 ml/min), therapy should be initiated with a dose of 4 mg silodosin once daily, after which, taking into account the individual response of the body, the dose may be increased to 8 mg once daily after 1 week of treatment. The use of the drug in the treatment of patients with severe renal impairment (creatinine clearance ≥ 30 ml/min) is not recommended.

Patients with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. Since there is no clinical experience in patients with severe hepatic impairment, the drug is not recommended for use in this patient population.

Children: Do not use in pediatric practice.

Overdose

Silodosin has been evaluated at doses up to 48 mg/day in healthy male volunteers. The dose-limiting adverse reaction was orthostatic hypotension.

If the drug intake has occurred recently, it is recommended to induce vomiting or perform gastric lavage. If an overdose of silodosin is accompanied by hypotension, it is necessary to provide the patient with cardiovascular support. Dialysis is not advisable, since silodosin in the body is almost completely bound to blood proteins (96.6%).

Adverse reactions

The most common adverse reactions reported during silodosin therapy in placebo-controlled clinical trials and during long-term use were ejaculation disorders, such as retrograde ejaculation and anejaculation (reduced or absent ejaculation), with an incidence of 23%. This may temporarily affect male fertility. However, it returns within a few days after discontinuation of treatment.

The table below lists the adverse reactions reported in all clinical trials and post-marketing experience, by MedDRA system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/100);

1 Adverse reaction data are derived from spontaneous reports during post-marketing use worldwide (frequency calculated taking into account cases reported in phase I–IV clinical trials and non-interventional studies).

Orthostatic hypotension: The incidence of orthostatic hypotension in placebo-controlled clinical trials was 1.2% with silodosin and 1.0% with placebo. Orthostatic hypotension may cause syncope (see section 4.4).

Reporting adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Expiration date

3 years.

Storage conditions

Store in the original package to protect from light.

Packaging

For 4 mg dosage: 10 capsules in a blister; 3 blisters in a cardboard box.

For 8 mg dosage: 10 capsules in a blister; 3 or 9 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Rontis Gelas Medical and Pharmaceutical Products S. AND.

Location of the manufacturer and its business address

Larissa Industrial Zone, P/O 3012, Larissa, 41 500, Greece.