Urief

Each film-coated tablet also contains the following excipients: Low substituted hydroxypropylcellulose, hydroxypropylcellulose, corn starch, magnesium stearate, talc, D-mannitol, hypromellose, titanium oxide and carnauba wax.
Silodosin is (-)-l-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-1H-indole-7-carboxamide.
It has a molecular formula of C₂₅H₃₂F₃N₃O₄ and a molecular weight of 495.53.
Silodosin is freely soluble in methanol and ethanol (99.5), and very slightly soluble in water with a melting point of 105-109°C.
Silodosin has a partition coefficient, distribution ratio (l-octanol/buffer) of 4.1 x 10^-3 at pH 2.8, 1.7 at pH 6 and 5 x 10² at pH 9.7.

Pharmacology: Pharmacodynamics: Mechanism of Action: By blocking the sympathetic nervous system, which mediates the α_1A-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.
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 α_1A-adrenergic receptor subtype.
Effect on Prostate Gland: In a receptor-binding assay using human prostate membrane specimens, silodosin showed a high affinity to the α_1A-adrenergic receptor subtype.
Silodosin inhibited noradrenalin-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 noradrenalin-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.
Clinical Studies: Phase II Double-Blind Comparative Study: When Urief 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 1).

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Phase III Double-Blind Comparative Study: When Urief 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 (see Figure 1 and Table 2). 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 Week 1 and an improvement effect was also observed in patients whose symptoms were severe.

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Long-Term Administration Study: In a long-term administration study, Urief 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 healthy adult males, respectively, plasma concentrations and pharmacokinetic parameters of silodosin (tablet or capsule) are shown in Table 3 and Figure 2 (see Table 3 and Figure 2).
It was demonstrated that the silodosin tablet of 4 mg and capsule of 4 mg are biologically equivalent.

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Data are expressed as mean±SD (n=27): When a single oral dose of Urief capsule was administered to healthy adult male volunteers (6 subjects/group) at doses ranging from 0.5-12 mg, plasma concentrations of silodosin increased dose-dependently and C_max and AUC_0-∞, showed linearity. The time course of changes in plasma concentrations of silodosin following a single oral administration of Urief capsule at a dose of 2 or 4 mg is shown in Figure 3 (see Figure 3).

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Data are expressed as mean±SD (n=6): When Urief capsule were administered orally twice daily for 7 days (once daily on days 1 and 7) at a dose of 4 mg/dose in 5 healthy adult male volunteers, plasma concentrations of silodosin reached a steady state on day 3. The accumulation factor relative to the 1st dose was 1.1-fold. (See Table 4.)

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Pharmacokinetic parameters following repeated administration are shown as the results obtained from the time course of changes in concentration on day 7 less the cumulative concentration from days 0-6.
When a single Urief capsule 4-mg dose was administered orally to 12 elderly males (age range: 65-75 years) postprandially, no obvious differences in the pharmacokinetic profile were observed compared to that in 9 non-elderly (age range: 21-31 years) males. The pharmacokinetic parameters in elderly males who received treatment with Urief capsule are shown in Table 5.

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When a single Urief capsule 4-mg dose was administered orally to 11 healthy adult male volunteers 30 min postprandially or under fasting conditions, the C_max, AUC_0-48hr, T_max and half-life (t_¹/2) following postprandial administration (or under fasting conditions) were 23 (28) ng/mL, 128.8 (135.9) ng·hr/mL, 2.1 (1.4) hrs and 6 (4.7) hrs, respectively (see Table 6).

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The clearance and distribution volume following administration of silodosin solution (2 mg) to 11 healthy adult male volunteers by IV infusion over 4 hrs were 167±33.8 mL/min and 49.5±17.3 L, respectively. The bioavailability following a single oral administration of Urief 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 metabolized 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 AUC_0-12hr of silodosin and its glucuronide and oxidized metabolites relative to the AUC_0-12hr of total radioactivity in plasma was 24, 21.9 and 34.9%, respectively. Other metabolites accounted for no more than 5%. In the 240-hr 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 hrs after a single Urief capsule 4-mg dose 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 oxidized 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 Urief 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 hrs post-dose were 24.8±8 and 7.4±3.3 ng/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 Not Marketed in Japan) Co-Administration: When 16 healthy male volunteers (non-Japanese) who were receiving ketoconazole 200 mg (orally) once daily for 4 days were co-administered a single Urief capsule 4-mg dose (orally) on day 2, C_max and AUC_0-∞ of silodosin increased 3.7- and 2.9-fold, respectively, compared to when silodosin alone was administered.
Digoxin Co-Administration: When Urief capsule (4 mg, twice daily) was co-administered orally with digoxin (0.25 mg, once daily) for 8 days to 16 healthy male volunteers (non-Japanese), it was confirmed that Urief capsule has no effect on the pharmacokinetic profile of digoxin.
Pharmacokinetics in Patients with Impaired Renal Function: When a single Urief capsule 4-mg dose was administered orally to 6 patients with impaired renal function [creatinine clearance (CrCl): 27-49 mL/min] and 7 volunteers with normal renal function (CrCl: 125-176 mL/min), the total plasma concentration of silodosin was increased (C_max: 3.1-fold; AUC_0-∞: 3.2-fold) 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 (C_max: 1.5-fold; AUC_0-∞: 2-fold), 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 7).

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Bladder outlet obstruction associated with benign prostatic hyperplasia.

Adults: 4 mg of silodosin twice daily after breakfast and evening meals.
The dosage may be reduced according to the patient's conditions.

Silodosin was evaluated at dose 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 protein bound (96.6%).

Hypersensitivity to silodosin or to any of the excipients of Urief.

Urief 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 Adverse Reactions.)
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.)
Careful Administration: Urief should be administered with care in the following patients: Patients with orthostatic hypotension. Symptoms may be aggravated.
Patients with impaired hepatic function. Elevated plasma drug concentrations may occur as previously mentioned.
Patients with impaired renal function. Elevated plasma drug concentrations have been reported as previously mentioned.
Patients treated with phosphodiesterase-5 inhibitors. (See Interactions.)
Important Precautions: Abnormal ejaculation (eg, retrograde ejaculation) has been reported. Therefore, Urief 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.
Prior to commencement of treatment with Urief, the patient should be asked whether they are taking any hypotensive drugs and, in the event that any hypotensive drugs are used, attention should be paid to changes in blood pressure while using Urief. If a decrease in blood pressure occurs, appropriate therapeutic actions eg, a dosage reduction or discontinuation of treatment should be taken.
It should be borne in mind that treatment with Urief does not eliminate the cause of the disease, but gives symptomatic relief. If treatment with Urief does not result in the expected effect, consideration should be given to other appropriate therapeutic measures eg, surgery.
Other Precautions: It has been reported that intraoperative floppy iris syndrome (IFIS) attributable to α1-blocking effect had been observed in patients who are currently receiving treatment with an α1-blocker or who have previously received such treatment.
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.
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 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.
Effects on the Ability to Drive or Operate Machinery: The symptom eg, dizziness may occur. Therefore, the patient should be advised to exercise caution when engaging in hazardous activities eg, working at heights or driving a car.
Use in pregnancy & lactation: Not applicable as silodosin is intended for male patients only.
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 eg, start administration at a low dose (2 mg/dose). (See Dosage & Administration.)

Not applicable as silodosin is intended for male patients only.

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 (eg, retrograde ejaculation) in 150 (17.2%) patients, thirst in 50 (5.7%) patients, diarrhea in 35 (4%) 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, lightheaded 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 (eg, retrograde ejaculation) was reported in 39 (22.3%) of 175 patients.
Clinically Significant Adverse Reactions: Syncope, Unconsciousness (Incidence Unknown): Since a transient unconsciousness associated with hypotension etc, may occur, patients should be carefully monitored and in the event of any abnormalities, treatment with Urief should be discontinued and appropriate therapeutic action taken.
Impaired Hepatic Function, Jaundice (Both Incidence Unknown): 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 eg, discontinuation of Urief should be taken.
Other Adverse Reactions: The following adverse reactions may occur. Therefore, if any abnormalities are observed, appropriate therapeutic measures eg, dosage reduction or discontinuation of treatment should be taken. See Table 8.

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Silodosin is metabolized mainly by cytochrome P450 3A4 (CYP3A4), UDP-glucuronosyl-transferases (UGTs), alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). (See Pharmacology: Pharmacokinetics under Actions.)
Co-administration with potent inhibitors of CYP3A4 activity blocks the metabolism of silodosin. This may result in elevated plasma drug concentrations. (See Table 9.)

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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 eg, mediastinitis.

Store at room temperature not exceeding 30°C. Protect from light.
Shelf-Life: 3 years.

Drugs for Bladder & Prostate Disorders

G04CA04 - silodosin ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.

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