Urief

Urief

silodosin

Manufacturer:

Eisai

Distributor:

DKSH
Full Prescribing Info
Contents
Silodosin.
Description
(See Table 1.)

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Excipients/Inactive Ingredients: Hydroxypropylcellulose, Corn starch, Magnesium stearate, Talc, D-mannitol, Hypromellose, Titanium Oxide, Carnauba Wax.
Action
Pharmacology: Pharmacodynamics: Pharmacological Effects: Effects in human tissue: Affinity to α-adrenergic receptors in the sympathetic nervous system: In a receptor-binding assay on human α1-adrenergic receptors, silodosin showed a high affinity to the α1A-adrenergic receptor subtype.
Effect on prostate gland: In a receptor-binding assay using human prostate membrane specimens, silodosin showed a high affinity to the α1A-adrenergic receptor subtype.
Silodosin inhibited noradrenaline-induced contractions of human prostate smooth muscle.
Effects in animals: Effect on lower urinary tract tissue (prostate, urethra, and trigone of bladder): Silodosin exhibited a potent antagonistic action against noradrenaline-induced contractions in isolated rabbit prostate, urethra, and trigone of bladder.
Effect on urethral pressure: In anesthetized male rats, phenylephrine-induced increases in urethral pressure in the region of the prostate were selectively inhibited by silodosin. The inhibitory dose was lower than hypotensive dose.
In anesthetized male dogs, increased urethral pressure in the region of the prostate due to electrical stimulation of the hypogastric nerve was also selectively inhibited by silodosin. The inhibitory dose was lower than hypotensive dose.
Effect in prostatic hypertrophy model: In a male rat prostatic hypertrophy model prepared by administration of sex hormone, bladder irritation symptoms associated with urinary retention were inhibited.
Mechanism of Action: By blocking the sympathetic nervous system through the α1A-adrenoceptor subtype which is distributed in lower urinary tract tissue (prostate, urethra, and trigone of bladder), silodosin reduces smooth muscle tone of lower urinary tract tissue and inhibits increases in urethral pressure, thereby improving lower urinary tract symptoms associated with benign prostatic hyperplasia.
Clinical Studies: Phase II Double-Blind Comparative Study: When silodosin capsule at a dose of 2 or 4 mg, or placebo was administered orally twice daily for 4 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, subjective symptoms (total I-PSS) were significantly improved in the 4 mg group compared to the placebo group (see Table 2).

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Phase III Double-blind Comparative Study: When silodosin capsule at a dose of 4 mg or placebo was administered orally twice daily for 12 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, the total I-PSS in the silodosin and placebo groups on completion of the study showed a decrease of 8.3 and 5.3 points, respectively, compared to baseline (Figure 1, Table 3). The percentage (%) of patients in the silodosin and placebo groups whose total I-PSS improved by at least 25% compared to baseline was 76.4% (133/174 patients) and 50.6% (45/89 patients), respectively. The percentage (%) of patients in the silodosin and placebo groups whose symptoms improved to mild (total I-PSS: < 8) was 47.7% (83/174 patients) and 31.5% (28/89 patients), respectively. In the silodosin group, an improvement in subjective symptoms was seen from as early as after one week of treatment and an improvement effect was also observed in patients whose symptoms were severe. (See Figure 1 and Table 3.)

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Long-term Administration Study: In a long-term administration study, silodosin capsule was administered at a dose of 4 mg twice daily for 52 weeks to 364 patients with lower urinary tract symptoms associated with benign prostatic hypertrophy. A continuous improvement effect and drug safety were reported and stable subjective symptoms (total I-PSS) and improvement in maximum urine flow rate were observed.
Pharmacokinetics: Absorption and Plasma Concentrations: When a single 4 mg dose of silodosin (tablet or capsule) was administered orally to 13 and 14 fasted healthy adult males, respectively, plasma concentrations and pharmacokinetic parameters of silodosin (tablet or capsule) are shown in Table 4.
It was demonstrated that the silodosin tablet of 4 mg and capsule of 4 mg are biologically equivalent. (See Table 4.)

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When a single oral dose of silodosin capsule was administered to healthy adult male volunteers (6 subjects/group) at doses ranging from 0.5 to 12 mg, plasma concentrations of silodosin increased dose-dependently, and Cmax and AUC0-∞ showed linearity. The time course of changes in plasma concentrations of silodosin following a single oral administration of URIEF Cap. at a dose of 2 or 4 mg is shown in Figure 2. (See Figure 2.)

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When silodosin capsule was administered orally twice daily for 7 days (once daily on days 1 and 7) at a dose of 4 mg/dose to 5 healthy adult male volunteers, plasma concentrations of silodosin reached a steady state on day 3. The accumulation factor relative to the first dose was 1.1-fold. (See Table 5.)

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When a single 4 mg dose of silodosin capsule was administered orally to 12 elderly males (age range: 65 to 75 years) postprandially, no obvious differences in the pharmacokinetic profile were observed compared to that in 9 non-elderly (age range: 21 to 31 years) males. The pharmacokinetic parameters in elderly males who received treatment with silodosin capsule are shown in Table 6. (See Table 6.)

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When a single 4 mg dose of silodosin capsule was administered orally to 11 healthy adult male volunteers 30 min postprandially or under fasting conditions, the Cmax, AUC0-48hr, Tmax, and t½ following postprandial administration (or under fasting conditions) were 23.0 (28.0) ng/mL, 128.8 (135.9) ng·hr/mL, 2.1 (1.4) hr, and 6.0 (4.7) hr, respectively (see Table 7).

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Distribution: The clearance and distribution volume following administration of silodosin solution (2 mg) to 11 healthy adult male volunteers by intravenous infusion over 4 hr were 167.0±33.8 mL/min and 49.5±17.3 L, respectively. The bioavailability following a single oral administration of silodosin capsule at a dose of 4 mg was 32.2%.
Protein Binding: In an in vitro study, the human plasma-protein binding rate of silodosin was 95.6 % (at a concentration of 100 ng/mL) and the main binding protein was α1-acid glycoprotein.
Metabolism and Excretion: Silodosin was metabolised mainly by CYP3A4, UGTs, ADH, and ALDH, with the major metabolites in plasma being a glucuronide and an oxidized metabolite of silodosin. When a single 8 mg dose of 14C-labeled silodosin solution was administered orally to 6 healthy male non-Japanese volunteers, the AUC0-12hr of silodosin and its glucuronide and oxidized metabolites relative to the AUC0-12hr of total radioactivity in plasma was 24.0, 21.9, and 34.9%, respectively. Other metabolites accounted for no more than 5%. In the 240-hour period after dosing, 33.5 and 54.9% of administered radioactivity was excreted in urine and feces, respectively.
The cumulative excretion in urine 0-48 hr after a single 4mg dose of silodosin capsule was administered orally to 12 elderly and 9 non-elderly male volunteers was 2.3 and 2.4% for silodosin, 1.6 and 1.8% for its glucuronide metabolite, and 4.5 and 4.9% for its oxidised metabolite, respectively.
Pharmacokinetics in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia: In an exploratory population pharmacokinetic analyses (n=258) of a long-term administration study with silodosin capsule in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, the estimated plasma concentrations of silodosin (mean±SD) at steady state 2 and 12 hours post-dose were 24.8±8.0 and 7.4±3.3ng/mL, respectively.
An analysis of variable factors in relation to plasma concentrations of silodosin suggested that silodosin clearance is affected by body weight, age, CRP, ALT (GPT), and serum creatinine and distribution volume by body weight, age, CRP, and ALT (GPT). Of these factors, it was concluded that ALT (GPT) had the most effect on plasma concentrations of silodosin and it was suggested that, as a result of increased levels of ALT (GPT) (23→83 IU/L), silodosin clearance and distribution volume may decrease by approximately 47 and 27%, respectively.
Drug Interaction(s): Non-Japanese data: Ketoconazole (oral preparation) coadministration: When 16 healthy male volunteers (non-Japanese) who were receiving 200 mg of ketoconazole (p.o.) once daily for 4 days were coadministered a single 4 mg dose of silodosin capsule (p.o.) on day 2, Cmax and AUC0-∞ of silodosin increased 3.7- and 2.9-fold, respectively, compared to when silodosin alone was administered.
Digoxin coadministration: When silodosin capsule (4 mg, twice daily) was coadministered orally with digoxin (0.25 mg, once daily) for 8 days to 16 healthy male volunteers (non-Japanese), it was confirmed that silodosin capsule has no effect on the pharmacokinetic profile of digoxin.
Pharmacokinetics in Patients with Impaired Renal Function: When a single 4 mg dose of silodosin capsule was administered orally to 6 patients with impaired renal function (creatinine clearance: 27-49 mL/min) and 7 volunteers with normal renal function (creatinine clearance: 125-176 mL/min), the total plasma concentration of silodosin was increased (Cmax: 3.1-fold higher; AUC0-∞: 3.2-fold higher) in patients with impaired renal function compared to that in the volunteer group.
This increase in total plasma concentration of silodosin may be attributable to protein binding with serum α1-acid glycoprotein, with a high correlation between total plasma concentration of silodosin and serum concentration of α1-acid glycoprotein observed. It should be noted that the increase in the plasma concentration of unbound silodosin (Cmax: 1.5-fold higher ; AUC0-∞: 2.0-fold higher), which is considered to have a direct bearing on the manifestation of drug effect and incidence of adverse reactions associated with silodosin, was less than that for the total drug concentration (see Table 8).

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Indications/Uses
Bladder outlet obstruction associated with benign prostatic hyperplasia in patients ≥50 years.
Precautions: URIEF Tablet is associated with a high incidence of adverse reactions and abnormal ejaculation is reported frequently as a characteristic adverse reaction. URIEF Tablet should be used after careful consideration is given to the risks associated with its use and carefully explaining the adverse reactions to the patient. (See Important Precautions under Precautions and Adverse Reactions.)
Dosage/Direction for Use
The adult dosage for oral use is 4 mg of silodosin twice daily after breakfast and evening meal. The dosage may be reduced according to the patient's conditions.
Precautions: The plasma concentration of silodosin may be elevated in patients with impaired hepatic function. It has been reported that plasma concentration of silodosin is increased in patients with impaired renal function. Therefore, starting treatment at a low dose (2 mg/dose) while observing the condition of the patient, for instance, should be considered. (See Pharmacology: PHARMACOKINETICS under Actions.)
Overdosage
Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse reaction was postural hypotension. If ingestion is recent, induction of vomiting or gastric lavage may be considered. Should overdose of silodosin lead to hypotension, cardiovascular support has to be provided. Dialysis is unlikely to be of significant benefit since silodosin is highly (96.6 %) protein bound.
Contraindications
Hypersensitivity to any of the components of Urief Tablets.
Special Precautions
Careful Administration (Urief Tablets should be administered with care in the following patients): Patients with orthostatic hypotension. [The symptoms may be aggravated.]
Patients with impaired hepatic function. [Elevated plasma drug concentrations may occur. (See Precautions under Dosage & Administration.)]
Patients with impaired renal function. [Elevated plasma drug concentrations have been reported. (See Precautions under Dosage & Administration.)]
Patients treated with phosphodiesterase-5 inhibitors. (See INTERACTIONS.)
Important Precautions: Abnormal ejaculation (e.g. retrograde ejaculation) has been reported. Therefore, Urief Tablets should be used after obtaining the understanding of patients by carefully explaining the risk of abnormal ejaculation. (See ADVERSE REACTIONS.)
Orthostatic hypotension may occur. Therefore, caution should be exercised regarding fluctuations in blood pressure due to changes in body posture.
The symptom such as dizziness may occur. Therefore, the patient should be advised to exercise caution when engaging in hazardous activities such as working at heights or driving a car.
Prior to commencement of treatment with Urief Tablets, the patient should be asked whether they are taking any hypotensive drugs and, in the event that any hypotensive drug are used, attention should be paid to changes in blood pressure while using Urief Tablets. If a decrease in blood pressure occurs, appropriate therapeutic actions, such as a dosage reduction or discontinuation of treatment, should be taken.
It should be borne in mind that treatment with Urief Tablets does not eliminate the cause of the disease, but gives symptomatic relief. If treatment with Urief Tablets does not result in the expected effect, consideration should be given to other appropriate therapeutic measures such as surgery.
Precautions concerning use: Precaution in dispensing: Patients should be instructed to press the tablet out of a press-through package (PTP) and take it.
[It has been reported that, if the PTP sheet is swallowed, the hard and sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.]
Other precautions: Intraoperative Floppy Iris Syndrome (IFIS): IFIS (a variant of small pupil syndrome) has been observed during cataract surgery in some patients on α1-blockers or previously treated with α1-blockers. During pre-operative assessment, eye surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Urief Tablets, in order to ensure that appropriate measures will be in place to manage IFIS during surgery.
In a 104-week administration study in mice, it has been reported that the frequency of seminal vesicle dilatation was increased at doses of 20 mg/kg/day or more.
In a study on fertility and early embryogenesis until implantation in rats, it has been reported that deciduation of sperm cells in seminiferous tubules was observed at doses of 200 mg/kg/day or more and atrophy/degeneration of seminiferous tubules as well as decreased sperm survival and sperm count were observed at a dose of 600 mg/kg/day.
Use in the Elderly: The elderly often have reduced physiological function. If hepatic or renal function is reduced, the elderly should be treated while carefully monitoring the condition of the patient, such as start administration at a low dose (2 mg/dose).
Use In Pregnancy & Lactation
Fertility: In clinical studies, the occurrence of ejaculation with reduced or no semen has been observed during treatment with silodosin, due to the pharmacodynamic properties of silodosin. Before starting treatment, the patient should be informed that this effect may occur, temporarily affecting male fertility.
Adverse Reactions
Adverse reactions of silodosin (capsule) were reported in 391 (44.8%) of a total of 873 patients with lower urinary tract symptoms in a clinical study conducted up to the time of approval. The most common adverse reactions included abnormal ejaculation (e.g. retrograde ejaculation) in 150 (17.2%) patients, thirst in 50 (5.7%) patients, diarrhea in 35 (4.0%) patients, loose stools in 34 (3.9%) patients, dizziness on standing up in 31 (3.6%) patients, nasal congestion in 29 (3.3%) patients, dizziness in 23 (2.6%) patients, light-headed feeling in 22 (2.5%) patients, and headache in 19 (2.2%) patients. Abnormal laboratory data were reported in 185 (21.7%) of a total of 853 patients. The most common events included increased triglycerides in 62 (7.4%) patients, increased CRP in 21 (3.9%) patients, increased ALT (GPT) in 20 (2.3%) patients, increased AST (GOT) in 19 (2.2%) patients, and increased γ-GTP in 19 (2.2%) patients. It should be noted that, in the phase III double-blind comparative study, abnormal ejaculation (e.g. retrograde ejaculation) was reported in 39 (22.3%) of 175 patients.
Adverse reactions were reported in 887 (11.3%) of a total of 7851 patients in drug-use survey and specified drug-use survey (long term) carried out after approval. The most common adverse reactions included abnormal ejaculation (e.g. retrograde ejaculation) in 255 (3.2%) patients, diarrhea and loose stools in 207 (2.6%) patients, dizziness and light-headed feeling in 85 (1.1%) patients, nasal congestion in 81 (1.0%) patients, thirst in 64 (0.8%) patients, dizziness on standing up in 60 (0.8%) patients. (At the end of the reexamination period).
Clinically significant adverse reactions: Syncope, loss of consciousness (less than 0.1%note)): Since transient loss of consciousness associated with hypotension may occur, the patient should be carefully monitored and, in the event of any abnormalities, treatment with this product must be discontinued and appropriate measures taken.
Impaired hepatic function, jaundice (less than 0.1%note)): Impaired hepatic function associated with increased AST (GOT), increased ALT (GPT) etc. or jaundice may occur, patients should be carefully monitored and, in the event of any abnormalities, appropriate measures, such as discontinuation of Urief Tablets should be taken.
Note): Based on the results of post-marketing surveillance after approval.
Other adverse reactions: The following adverse reactions may occur. Therefore, if any abnormalities are observed, appropriate therapeutic measures such as dosage reduction or discontinuation of treatment should be taken. (See Table 9.)

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Drug Interactions
Silodosin is metabolised mainly by cytochrome P450 3A4 (CYP3A4), UDP-glucuronosyltransferases (UGTs), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH). (See Pharmacology: Pharmacokinetics under Actions.)
Coadministration with potent inhibitors of CYP3A4 activity blocks the metabolism of silodosin. This may result in elevated plasma drug concentrations. (See Table 10.)

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Storage
Store in a tight container protected from light at room temperature not exceeding 30°C.
Shelf-Life: 3 years.
ATC Classification
G04CA04 - silodosin ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.
Presentation/Packing
FC tab 4 mg [white to pale yellowish white (scored)] x 3 x 10's.
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