Arylozin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARILLOSIN

Composition:

Active substance: silodosin;

1 capsule contains 4 mg or 8 mg of silodosin;

Excipients: mannitol, pregelatinized corn starch, sodium lauryl sulfate, glyceryl 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 the 4 mg strength — iron(III)-hydroxide-oxide (E172).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

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

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

Pharmacotherapeutic group. α-Adrenoreceptor antagonists. Silodosin.

ATC code G04CA04.

Pharmacological Properties

Pharmacodynamics

Silodosin is a highly selective agent, an antagonist of α1A-adrenoceptors, which are predominantly located in the prostate gland, bladder base, bladder neck, prostate capsule, and prostatic urethra. Blockade of α1A-adrenoceptors leads to relaxation of the smooth muscle in these areas, thereby increasing urinary flow rate without affecting the contractility of the detrusor smooth muscle. As a result, symptoms of irritation and obstruction caused by benign prostatic hyperplasia (BPH) are alleviated.

Silodosin has much lower affinity for α1B-adrenoceptors, which are primarily located in cardiovascular tissues.

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 symptom scores on the American Urological Association (AUA) scale is significantly better with silodosin at doses of 4 mg or 8 mg compared to placebo. Clinical studies conducted in the United States and Europe using silodosin 8 mg once daily demonstrated a significant reduction in both storage (irritative) and voiding (obstructive) symptoms of BPH compared to placebo, as assessed by the International Prostate Symptom Score (IPSS), after 12 weeks of treatment. In clinical trials conducted in Europe, silodosin 8 mg once daily was found to be at least as effective as tamsulosin 0.4 mg once daily. The frequency of positive response to treatment—defined as improvement in overall IPSS score—was significantly higher in the groups receiving silodosin and tamsulosin compared to placebo.

In the long-term open-label extension phase of these clinical trials, in which patients received silodosin for up to 1 year, the symptomatic improvement observed at week 12 was maintained for over 1 year.

In a phase IV clinical study conducted in Europe, treatment response according to the International Prostate Symptom Score was observed in 77.1% of patients. Approximately half of the patients with the most bothersome symptoms—namely nocturia, increased urinary frequency, weak stream, urgency, terminal dribbling, and incomplete bladder emptying—reported symptom improvement, as assessed by the International Continence Society (ICS) male questionnaire.

In all clinical trials conducted with silodosin, no clinically significant reduction in blood pressure in the supine position was observed.

Silodosin at doses of 8 mg and 24 mg daily did not have a statistically significant effect on ECG intervals or cardiac repolarization compared to placebo.

Pharmacokinetics

The pharmacokinetic characteristics of silodosin and its major metabolites were evaluated in male adult patients, healthy or with BPH, after single and/or multiple doses ranging from 0.1 mg to 48 mg daily. Within this dose range, the pharmacokinetic characteristics of silodosin change linearly.

Exposure to the main metabolite, silodosin glucuronide (KMD-3213G), in plasma at steady state is three times higher than exposure to the parent drug. Silodosin and its glucuronide reach steady-state concentrations after 3 days and 5 days of treatment, respectively.

Absorption

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

In vitro studies using Caco-2 cells have shown that silodosin is a substrate of P-glycoprotein.

When administered with food, Cmax is reduced by approximately 30%, tmax is prolonged by about 1 hour, while no change in AUC is observed. After oral administration of 8 mg 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%.

Biotransformation

Silodosin is metabolized primarily via glucuronidation (UGT2B7), alcohol and aldehyde dehydrogenase activity, and oxidation, mainly by CYP3A4. The major metabolite in plasma is the conjugated silodosin glucuronide (KMD-3213G), which has confirmed activity in vitro and is characterized by a longer half-life (approximately 24 hours); its plasma concentration is about four times higher than that of silodosin itself. In vitro data indicate that silodosin does not inhibit or induce cytochrome P450 isoenzymes.

Elimination

Approximately 33.5% of silodosin is excreted in urine and 54.9% in feces within 7 days after oral administration. The total clearance of silodosin is approximately 0.28 L/h/kg. Silodosin is excreted predominantly as metabolites, with only a very small fraction excreted unchanged in urine. The terminal half-life of the unchanged drug and its glucuronides is approximately 11 hours and 18 hours, respectively.

Pharmacokinetics in Special Patient Populations

Elderly patients. The pharmacokinetic characteristics of silodosin and its major metabolites are independent of patient age. 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 pharmacokinetic characteristics of silodosin were similar in patients with moderate hepatic impairment (Child-Pugh class 7–9 points) and in healthy volunteers. These results should be interpreted with caution, as the patients had normal biochemical parameters indicating normal metabolic function and were classified as having 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. Single-dose studies showed that Cmax and AUC of unbound silodosin were increased by 1.6- and 1.7-fold, respectively, in patients with mild or moderate renal impairment compared to patients with normal renal function. In patients with severe renal impairment, Cmax increased by 2.2-fold and AUC by 3.7-fold. Pharmacokinetic parameters of the main metabolites—silodosin glucuronide and KMD-3293—also increased.

Plasma concentrations of silodosin after 4 weeks of treatment in patients with mild renal impairment were similar to those in patients with normal renal function, whereas in patients with moderate renal impairment, drug concentrations doubled.

An overall review of safety data indicates 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, dose adjustment is not required in patients with mild renal impairment. Due to limited data on the use of silodosin in patients with moderate renal impairment, the initial recommended dose is 4 mg. The use of silodosin in patients with severe renal impairment is not recommended.

Clinical characteristics

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

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

Interaction with other medicinal products and other forms of interaction

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

Alpha-blockers

There is insufficient safety data regarding the concomitant use of silodosin with α-adrenoreceptor antagonists. Therefore, concomitant administration with other α-adrenoreceptor antagonists is not recommended (see section "Special precautions for use").

Inhibitors of CYP3A4 isoenzymes

Results from drug interaction studies have shown that co-administration with strong inhibitors of CYP3A4 isoenzymes (ketoconazole, 400 mg) increases the maximum plasma concentration of silodosin by 3.7-fold and the exposure (AUC value) by 3.1-fold. Concomitant use with strong inhibitors of CYP3A4 isoenzymes (such as ketoconazole, itraconazole, or ritonavir) is not recommended.

When silodosin was co-administered with moderate inhibitors of CYP3A4 isoenzymes, such as diltiazem, an increase in AUC of approximately 30% was observed, while Cmax and elimination half-life remained unchanged. This change is not clinically significant; therefore, dose adjustment is not required.

Phosphodiesterase type 5 inhibitors (PDE-5)

Minimal pharmacodynamic interaction was observed when sildenafil 100 mg or tadalafil 20 mg were co-administered, which did not cause clinically significant reductions in systolic or diastolic blood pressure according to orthostatic challenge tests (upright vs. supine position). In patients aged over 65 years, mean reductions at various time points ranged between 5 and 15 mm Hg (systolic) and 0 and 10 mm Hg (diastolic). Positive orthostatic tests were only slightly more frequent during concomitant use; however, no cases of symptomatic orthostatic hypotension or dizziness were reported. Patients receiving silodosin concomitantly with PDE-5 inhibitors should be monitored to avoid potential adverse reactions.

Antihypertensive agents

In clinical trial programs, many patients received concomitant therapy with antihypertensive agents (mostly drugs affecting the renin-angiotensin system, beta-blockers, calcium antagonists, and diuretics) without increased risk of orthostatic hypotension. However, caution is advised when initiating concomitant antihypertensive therapy; patient monitoring is necessary to detect possible adverse effects.

Digoxin

When administered concomitantly with silodosin 8 mg once daily, steady-state digoxin concentrations (a P-glycoprotein substrate) were only slightly altered. Dose adjustment is not required.

Special precautions for use

Intraoperative floppy iris syndrome

Intraoperative floppy iris syndrome (a variant of the intraoperative miosis syndrome) has been observed during cataract surgery in some patients who are currently or were previously treated with α1-blockers. This complication increases the risk of procedural complications during surgery.

Patients should not initiate treatment with silodosin prior to planned cataract surgery. It is recommended to discontinue therapy with α1-blockers 1–2 weeks before cataract surgery; however, the optimal duration of treatment discontinuation prior to cataract surgery and the benefits of such discontinuation have not yet been established.

During the preoperative period for cataract surgery, surgeons and ophthalmologists should determine whether the patient is currently or has previously taken silodosin in order to take appropriate measures to prevent intraoperative floppy iris syndrome during surgery.

Orthostatic effects

Orthostatic effects during treatment with silodosin are very rare. However, in some patients, a decrease in blood pressure may occur, which in individual cases may lead to loss of consciousness. In the presence of first signs of orthostatic hypotension (e.g. orthostatic dizziness), the patient should be seated or laid down until symptoms resolve. Silodosin therapy is not recommended for patients with orthostatic hypotension.

Renal function impairment

The use of silodosin in patients with severe renal impairment (creatinine clearance [CrCl] < 30 mL/min) is not recommended.

Hepatic function impairment

The use of silodosin in patients with severe hepatic impairment is not recommended due to insufficient data.

Prostate carcinoma

Since benign prostatic hyperplasia (BPH) and prostate carcinoma present with similar symptoms and both conditions may coexist, prostate carcinoma must be ruled out before initiating silodosin therapy for BPH. Digital rectal examination should be performed. Additionally, prostate-specific antigen (PSA) levels should be measured before starting treatment and monitored regularly during treatment.

Fertility

Silodosin treatment may lead to reduced or absent ejaculation during orgasm and may temporarily affect male fertility. Cases of retrograde ejaculation (orgasm with reduced or no ejaculation) have been reported in patients taking silodosin. This effect is reversible upon discontinuation of the drug.

Patients should be informed about the possibility of retrograde ejaculation prior to initiating therapy.

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

Use during pregnancy or breastfeeding

Silodosin is indicated only for treatment of male patients.

Ability to affect reaction rate while driving or operating machinery

Specific studies to assess the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Patients should be warned about the possible occurrence of symptoms related to orthostatic hypotension (such as dizziness) and advised to refrain from driving or operating machinery until they know how silodosin affects them.

Method of Administration and Dosage

For oral use in adults. The recommended dose is 8 mg once daily. For certain patient groups, the recommended dose is one 4 mg silodosin capsule once daily (see below).

The medication should be taken with food, preferably at the same time each day. The capsule must not be crushed—it should be swallowed whole, without chewing, with a glass of water.

Elderly patients. Dose adjustment is not required for elderly patients (see section "Pharmacokinetics").

Patients with renal impairment. Dose adjustment is not required in patients with mild renal impairment (creatinine clearance from ≥50 to <80 mL/min). In patients with moderate renal impairment (creatinine clearance from ≥30 to <50 mL/min), treatment should be initiated at 4 mg silodosin once daily. After one week of treatment, the dose may be increased to 8 mg once daily, depending on individual response. The use of the drug is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).

Patients with hepatic impairment. Dose adjustment is not required in patients with mild or moderate hepatic impairment. Since there is no clinical experience with the use of silodosin in patients with severe hepatic impairment, administration of the drug to these patients is not recommended.

Children. Not to be used in pediatric practice.

Overdose

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

If drug ingestion was recent, it is recommended to induce vomiting or perform gastric lavage. If silodosin overdose is accompanied by hypotension, cardiovascular support should be provided. Dialysis is not recommended, as silodosin is highly bound to plasma proteins (96.6%) in the body.

Adverse Reactions

The most commonly reported adverse reactions 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), occurring with a frequency of 23%. This may temporarily affect male fertility. However, fertility is restored within a few days after discontinuation of treatment.

The table below lists adverse reactions reported during all clinical trials and in the post-marketing period, organized by system organ class according to MedDRA [Medical Dictionary for Regulatory Activities] and by frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each group, reactions are listed in order of decreasing severity.

1 Data on adverse reactions were obtained from spontaneous reports during post-marketing use worldwide (frequency calculated based on cases reported in phases I–IV of clinical trials and non-interventional studies).

Orthostatic hypotension: the incidence of orthostatic hypotension in placebo-controlled clinical trials was 1.2% with silodosin treatment and 1.0% with placebo. Orthostatic hypotension may lead to syncope (see section "Special warnings and precautions for use").

Intraoperative floppy iris syndrome (a variant of intraoperative floppy iris syndrome) has been observed during cataract surgery (see section "Special warnings and precautions for use").

Reporting of suspected adverse reactions after medicine registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from light.

Packaging

Dosage of 4 mg: 10 capsules in a blister; 3 blisters in a cardboard box.

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

Prescription status. Prescription only.

Manufacturer. Rontis Hellas Medical and Pharmaceutical Products S.A.

Manufacturer's location and address of its place of business

Industrial Area of Larissa, P.O. Box 3012, Larissa, 41 500, Greece