Leaflet UROREC 8mg capsules

Each hard capsule contains 4 mg silodosin.

Each hard capsule contains 8 mg silodosin.

For the full list of excipients, see section 6.1.

Hard capsule.

Yellow, opaque, hard gelatin capsule, size 3 (approximately 15.9 x 5.8 mm).

White, opaque, hard gelatin capsule, size 0 (approximately 21.7 x 7.6 mm).

Treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in adult men.

The recommended dose is one capsule of Urorec 8 mg daily. For special patient populations, onecapsule of Urorec 4 mg daily is recommended (see below).

No dose adjustment is required in the elderly (see section 5.2).

No dose adjustment is required for patients with mild renal impairment (CLCR ≥ 50 to ≤ 80 mL/min).

A starting dose of 4 mg once daily is recommended in patients with moderate renal impairment(CLCR ≥ 30 to < 50 mL/min), which may be increased to 8 mg once daily after one week of treatment,depending on the individual patient’s response. The use in patients with severe renal impairment(CLCR < 30 mL/min) is not recommended (see sections 4.4 and 5.2).

No dose adjustment is required for patients with mild to moderate hepatic impairment.

As no data are available, the use in patients with severe hepatic impairment is not recommended (seesections 4.4 and 5.2).

There is no relevant use of Urorec in the paediatric population for the indication of benign prostatichyperplasia (BPH).

Oral use.

The capsule should be taken with food, preferably at the same time every day. The capsule should notbe broken or chewed but swallowed whole, preferably with a glass of water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

IFIS (a variant of small pupil syndrome) has been observed during cataract surgery in some patients onα1-blockers or previously treated with α1-blockers. This may lead to increased proceduralcomplications during the operation.

The initiation of therapy with silodosin is not recommended in patients for whom cataract surgery isscheduled. Discontinuing treatment with an α1-blocker 1-2 weeks prior to cataract surgery has beenrecommended, but the benefit and duration of stopping the therapy prior to cataract surgery has not yetbeen established.

During pre-operative assessment, eye surgeons and ophthalmic teams should consider whether patientsscheduled for cataract surgery are being or have been treated with silodosin, in order to ensure thatappropriate measures will be in place to manage IFIS during surgery.

The incidence of orthostatic effects with silodosin is very low. However, a reduction in blood pressurecan occur in individual patients, leading in rare cases to syncope. At the first signs of orthostatichypotension (such as postural dizziness), the patient should sit or lie down until the symptoms havedisappeared. In patients with orthostatic hypotension, treatment with silodosin is not recommended.

The use of silodosin in patients with severe renal impairment (CLCR <30 ml/min) is not recommended(see sections 4.2 and 5.2).

Since no data are available in patients with severe hepatic impairment, the use of silodosin in thesepatients is not recommended (see sections 4.2 and 5.2).

Since BPH and prostate carcinoma may present the same symptoms and can co-exist, patients thoughtto have BPH should be examined prior to starting therapy with silodosin, to rule out the presence ofcarcinoma of the prostate. Digital rectal examination and, when necessary, determination of prostatespecific antigen (PSA) should be performed before treatment and at regular intervals afterwards.

Treatment with silodosin leads to a decrease in the amount of semen released during orgasm that maytemporarily affect male fertility. This effect disappears after discontinuation of silodosin (seesection 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to sayessentially ‘sodium-free’.

Silodosin is metabolised extensively, mainly via CYP3A4, alcohol dehydrogenase and UGT2B7.

Silodosin is also a substrate for P-glycoprotein. Substances that inhibit (such as ketoconazole,itraconazole, ritonavir or cyclosporine) or induce (such as rifampicin, barbiturates, carbamazepine,phenytoin) these enzymes and transporters may affect the plasma concentrations of silodosin and itsactive metabolite.

There is inadequate information about the safe use of silodosin in association with otherα-adrenoreceptor antagonists. Consequently, the concomitant use of other α-adrenoreceptorantagonists is not recommended.

In an interaction study, a 3.7-fold increase in maximum silodosin plasma concentrations and a 3.1-foldincrease in silodosin exposure (i.e. AUC) were observed with concurrent administration of a potent

CYP3A4 inhibitor (ketoconazole 400 mg). Concomitant use with potent CYP3A4 inhibitors (such asketoconazole, itraconazole, ritonavir or cyclosporine) is not recommended.

When silodosin was co-administered with a CYP3A4 inhibitor of moderate potency such as diltiazem,an increase in silodosin AUC of approximately 30% was observed, but Cmax and half-life were notaffected. This change is clinically not relevant and no dose adjustment is required.

Minimal pharmacodynamic interactions have been observed between silodosin and maximum doses ofsildenafil or tadalafil. In a placebo-controlled study in 24 subjects 45-78 years of age receivingsilodosin, the co-administration of sildenafil 100 mg or tadalafil 20 mg induced no clinicallymeaningful mean decreases in systolic or diastolic blood pressure, as assessed by orthostatic tests(standing versus supine). In the subjects over 65 years, the mean decreases at the various time pointswere between 5 and 15 mmHg (systolic) and 0 and 10 mmHg (diastolic). Positive orthostatic testswere only slightly more common during co-administration; however, no symptomatic orthostasis ordizziness occurred. Patients taking PDE-5 inhibitors concomitantly with silodosin should be monitoredfor possible adverse reactions.

In the clinical study program, many patients were on concomitant antihypertensive therapy (mostlyagents acting on the renin-angiotensin system, beta-blockers, calcium antagonists and diuretics)without experiencing an increase in the incidence of orthostatic hypotension. Nevertheless, cautionshould be exercised when starting concomitant use with antihypertensives and patients should bemonitored for possible adverse reactions.

Steady state levels of digoxin, a substrate of P-glycoprotein, were not significantly affected byco-administration with silodosin 8 mg once daily. No dose adjustment is required.

Not applicable as silodosin is intended for male patients only.

In clinical studies, the occurrence of ejaculation with reduced or no semen has been observed duringtreatment with silodosin (see section 4.8), due to the pharmacodynamic properties of silodosin. Beforestarting treatment, the patient should be informed that this effect may occur, temporarily affectingmale fertility.

Urorec has minor or moderate influence on the ability to drive and use machines. Patients should beinformed about the possible occurrence of symptoms related to postural hypotension (such asdizziness) and should be cautioned about driving or operating machines until they know how silodosinwill affect them.

The safety of silodosin has been evaluated in four Phase II-III double-blind controlled clinical studies(with 931 patients receiving silodosin 8 mg once daily and 733 patients receiving placebo) and in twolong-term open-label extension phase studies. In total, 1,581 patients have received silodosin at a doseof 8 mg once daily, including 961 patients exposed for at least 6 months and 384 patients exposed for1 year.

The most frequent adverse reactions reported with silodosin in placebo controlled clinical studies andduring long-term use were ejaculatory disorders such as retrograde ejaculation and anejaculation(ejaculatory volume reduced or absent), with a frequency of 23%. This may temporarily affect malefertility. It is reversible within a few days upon discontinuation of treatment (see section 4.4).

In the table below, adverse reactions reported in all clinical studies and in the worldwidepost-marketing experience for which a reasonable causal relationship exists are listed by MedDRAsystem organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot beestimated from available data). Within each frequency grouping the observed adverse reactions arepresented in order of decreasing seriousness.

System organ Very Common Uncommon Rare Very rare Not knownclass common

Immune system Allergic-typedisorders reactionsincludingfacialswelling,swollentongue andpharyngealoedema1

Psychiatric Libidodisorders decreased

Nervous system Dizziness Syncopedisorders Loss ofconsciousness1

Cardiac Tachycardia1 Palpitations1disorders

Vascular Orthostatic Hypotension1disorders hypotension

Respiratory, Nasalthoracic and congestionmediastinaldisorders

Gastrointestinal Diarrhoea Nauseadisorders Dry mouth

Hepatobiliary Abnormaldisorders liver functiontests1

System organ Very Common Uncommon Rare Very rare Not knownclass common

Skin and Skin rash1,subcutaneous Pruritus1tissue disorders Urticaria1

Drugeruption1

Reproductive Ejaculatory Erectilesystem and disorders, dysfunctionbreast includingdisorders retrogradeejaculation,anejaculation

Injury, Intraoperativepoisoning and Floppy Irisprocedural Syndromecomplication1 - adverse reactions from spontaneous reporting in the worldwide post-marketing experience (frequencies calculated fromevents reported in Phase I-IV clinical trials and non-interventional studies).

The incidence of orthostatic hypotension in placebo-controlled clinical studies was 1.2% withsilodosin and 1.0% with placebo. Orthostatic hypotension may occasionally lead to syncope (seesection 4.4).

IFIS has been reported during cataract surgery (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limitingadverse reaction was postural hypotension. If ingestion is recent, induction of vomiting or gastriclavage may be considered. Should overdose of silodosin lead to hypotension, cardiovascular supporthas to be provided. Dialysis is unlikely to be of significant benefit since silodosin is highly (96.6%)protein bound.

Pharmacotherapeutic group: Urologicals, alpha-adrenoreceptor antagonists, ATC code: G04CA04.

Silodosin is highly selective for α1A-adrenoreceptors that are primarily located in the human prostate,bladder base, bladder neck, prostatic capsule and prostatic urethra. Blockade of theseα1A-adrenoreceptors causes smooth muscle in these tissues to relax, thus decreasing bladder outletresistance, without affecting detrusor smooth muscle contractility. This causes an improvement of bothstorage (irritative) and voiding (obstructive) symptoms (Lower urinary tract symptoms, LUTS)associated with benign prostatic hyperplasia.

Silodosin has a substantially lower affinity for the α1B-adrenoreceptors that are primarily located in thecardiovascular system. It has been demonstrated in vitro that the α1A:α1B binding ratio of silodosin(162:1) is extremely high.

In a Phase II dose-finding, double-blind, placebo-controlled clinical study with silodosin 4 or 8 mgonce daily, a greater improvement in American Urologic Association (AUA) symptom index scorewas observed with silodosin 8 mg (-6.8 ± 5.8, n = 90; p = 0.0018) and silodosin 4 mg (-5.7 ± 5.5,n = 88; p = 0.0355) as compared to placebo (-4.0 ± 5.5, n = 83).

Over 800 patients with moderate to severe symptoms of BPH (International Prostate Symptom Score,

IPSS, baseline value ≥13) received silodosin 8 mg once daily in two Phase III placebo-controlledclinical studies conducted in the United States and in one placebo- and active-controlled clinical studyconducted in Europe. In all studies, patients who did not respond to placebo during a 4-week placeborun-in phase were randomised to receive the study treatment. In all studies, patients treated withsilodosin had a greater decrease in both storage (irritative) and voiding (obstructive) symptoms of

BPH as compared to placebo as assessed after 12 weeks of treatment. Data observed in the

Intent-to-treat populations of each study are shown below:

IPSS IPSS IPSS

Total score Irritative symptoms Obstructive

Treatment No. of symptoms

Study arm patients Baseline Change Difference Change Difference Change Differencevalue from (95 % CI) from (95 % CI) from (95 % CI)(± SD) baseline vs vs vsplacebo baseline placebo baseline placebo

Silodosin 233 22 ± 5 -6.5

US-1 -2.8* -2.3 -0.9* -4.2 -1.9*

Placebo 228 21 ± 5 -3.6 (-3.9, -1.7)

- 1.4 (-1.4, -0.4) -2.2 (-2.6, -1.2)

Silodosin 233 21 ± 5 -6.3 -2.4 -3.9

US-2 -2.9* -1.0* -1.8*

Placebo 229 21 ± 5 -3.4 (-4.0, -1.8) -1.3 (-1.5, -0.6) -2.1 (-2.5, -1.1)

Silodosin 371 19 ± 4 -7.0 -2.3* -2.5 -0.7° -4.5 -1.7*(-3.2, -1.4) (-1.1, -0.2) (-2.2, -1.1)

Europe Tamsulosin 376 19 ± 4 -6.7 -2.0* -2.4 -0.6° -4.2 -1.4*(-2.9, -1.1) (-1.1, -0.2) (-2.0, -0.8)

Placebo 185 19 ± 4 -4.7 -1.8 -2.9

* p < 0.001 vs Placebo; ° p = 0.002 vs Placebo

In the active-controlled clinical study conducted in Europe, silodosin 8 mg once daily was shown to benon inferior to tamsulosin 0.4 mg once daily: the adjusted mean difference (95% CI) in the IPSS Total

Score between treatments in the per-protocol population was 0.4 (-0.4 to 1.1). The responder rate (i.e.improvement in the IPSS total score by at least 25%) was significantly higher in the silodosin (68%)and tamsulosin group (65%), as compared to placebo (53%).

In the long-term open-label extension phase of these controlled studies, in which patients receivedsilodosin for up to 1 year, the symptom improvement induced by silodosin at week 12 of treatmentwas maintained over 1 year.

In a Phase IV clinical trial performed in Europe, with a mean baseline IPSS total score of 18.9 points,77.1%were responders to silodosin (as assessed by a change from baseline in the IPSS total score of atleast 25%). Approximately half of the patients reported an improvement in the most bothersomesymptoms complained at baseline by the patients (i.e. nocturia, frequency, decreased stream, urgency,terminal dribbling and incomplete emptying), as assessed by the ICS-male questionnaire.

No significant reduction in supine blood pressure was observed in all clinical studies conducted withsilodosin.

Silodosin 8 mg and 24 mg daily had no statistically significant effect on ECG intervals or cardiacrepolarisation relative to placebo.

The European Medicines Agency has waived the obligation to submit the results of studies with

Urorec in all subsets of the paediatric population in BPH (see section 4.2 for information on paediatricuse).

The pharmacokinetics of silodosin and its main metabolites have been evaluated in adult male subjectswith and without BPH after single and multiple administrations with doses ranging from 0.1 mg to48 mg per day. The pharmacokinetics of silodosin is linear throughout this dose range.

The exposure to the main metabolite in plasma, silodosin glucuronide (KMD-3213G), at steady-stateis about 3-fold that of the parent substance. Silodosin and its glucuronide reach steady-state after3 days and 5 days of treatment, respectively.

Silodosin administered orally is well absorbed and absorption is dose proportional. The absolutebioavailability is approximately 32%.

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

Food decreases Cmax by approximately 30%, increases tmax by approximately 1 hour and has littleeffect on AUC.

In healthy male subjects of the target age range (n = 16, mean age 55 ± 8 years) after once-a-day oraladministration of 8 mg immediately after breakfast for 7 days, the following pharmacokineticparameters were obtained: Cmax 87 ± 51 ng/mL (sd), tmax 2.5 hours (range 1.0-3.0), AUC433 ± 286 ng * h/mL.

Silodosin has a volume of distribution of 0.81 L/kg and is 96.6% bound to plasma proteins. It does notdistribute into blood cells.

Protein binding of silodosin glucuronide is 91%.

Silodosin undergoes extensive metabolism through glucuronidation (UGT2B7), alcohol and aldehydedehydrogenase and oxidative pathways, mainly CYP3A4. The main metabolite in plasma, theglucuronide conjugate of silodosin (KMD-3213G), that has been shown to be active in vitro, has anextended half-life (approximately 24 hours) and reaches plasma concentrations approximately fourtimes higher than those of silodosin. In vitro data indicate that silodosin does not have the potential toinhibit or induce cytochrome P450 enzyme systems.

Following oral administration of 14C-labelled silodosin, the recovery of radioactivity after 7 days wasapproximately 33.5% in urine and 54.9% in faeces. Body clearance of silodosin was approximately0.28 L/h/kg. Silodosin is excreted mainly as metabolites, very low amounts of unchanged drug arerecovered in urine. The terminal half-life of parent drug and its glucuronide is approximately 11 hoursand 18 hours, respectively.

Exposure to silodosin and its main metabolites does not change significantly with age, even in subjectsof age over 75 years.

Silodosin has not been evaluated in patients less than 18 years of age.

In a single-dose study, the pharmacokinetics of silodosin was not altered in nine patients withmoderate hepatic impairment (Child-Pugh scores 7 to 9), compared to nine healthy subjects. Resultsfrom this study should be interpreted with caution, since enrolled patients had normal biochemistryvalues, indicating normal metabolic function, and they were classified as having moderate liverimpairment based on ascites and hepatic encephalopathy.

The pharmacokinetics of silodosin in patients with severe hepatic impairment has not been studied.

In a single-dose study, exposure to silodosin (unbound) in subjects with mild (n = 8) and moderaterenal impairment (n = 8) resulted, on average, in an increase of Cmax (1.6-fold) and AUC (1.7-fold)relative to subjects with normal renal function (n = 8). In subjects with severe renal impairment (n = 5)increase of exposure was 2.2-fold for Cmax and 3.7-fold for AUC. Exposure to the main metabolites,silodosin glucuronide and KMD3293, was also increased.

Plasma level monitoring in a Phase III clinical study showed that levels of total silodosin after 4 weeksof treatment did not change in patients with mild impairment (n = 70), compared to patients withnormal renal function (n = 155), while the levels were doubled on average in patients with moderateimpairment (n = 7).

A review of safety data of patients enrolled in all clinical studies does not indicate that mild renalimpairment (n = 487) poses an additional safety risk during silodosin therapy (such as an increase indizziness or orthostatic hypotension) as compared to patients with normal renal function (n = 955).

Accordingly, no dose adjustment is required in patients with mild renal impairment. Since only limitedexperience exists in patients with moderate renal impairment (n = 35), a lower starting dose of 4 mg isrecommended. In patients with severe renal impairment administration of Urorec is not recommended.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, carcinogenic, mutagenic and teratogenic potential. Effects in animals (affecting thethyroid gland in rodents) were observed only at exposures considered sufficiently in excess of themaximum human exposure, indicating little relevance to clinical use.

In male rats, decreased fertility was observed from exposures which were approximately twice theexposure at the maximum recommended human dose. The observed effect was reversible.

Urorec 4 mg and 8 mg hard capsules

Starch, pregelatinised (maize)

Mannitol (E421)

Magnesium stearate

Sodium laurilsulfate

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172) (4 mg capsules only)

Not applicable.

3 years.

Do not store above 30 °C.

Store in the original package in order to protect from light and moisture.

The capsules are provided in PVC/PVDC/aluminium foil blisters, packed in cartons.

Packs of 5, 10, 20, 30, 50, 90, 100 capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Ireland Ltd.

Raheens East

Ringaskiddy Co. Cork

Ireland

EU/1/09/608/001

EU/1/09/608/002

EU/1/09/608/003

EU/1/09/608/004

EU/1/09/608/005

EU/1/09/608/006

EU/1/09/608/007

EU/1/09/608/008

EU/1/09/608/009

EU/1/09/608/010

EU/1/09/608/011

EU/1/09/608/012

EU/1/09/608/013

EU/1/09/608/014

Date of first authorisation: 29/01/2010

Date of latest renewal: 18/09/2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.