Silodosin

1 INDICATIONS AND USAGE Silodosin capsule, a selective alpha-1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [see CLINICAL STUDIES (14)] . Silodosin capsule is not indicated for the treatment of hypertension. Silodosin capsule, an alpha-1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin capsule is not indicated for the treatment of hypertension. (1)

2 DOSAGE AND ADMINISTRATION 8 mg capsules taken orally once daily with a meal. (2.1) 4 mg capsules taken orally once daily with a meal for those with moderate renal impairment [Creatinine Clearance (CCr) 30 to 50 mL/min]. (2.2) 2.1 Dosing Information The recommended dose is 8 mg orally once daily with a meal. Patients who have difficulty swallowing pills and capsules may carefully open the silodosin capsule and sprinkle the powder inside on a tablespoonful of applesauce. The applesauce should be swallowed immediately (within 5 minutes) without chewing and followed with an 8 oz glass of cool water to ensure complete swallowing of the powder. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any powder/applesauce mixture should be used immediately (within 5 minutes) and not stored for future use. Subdividing the contents of a silodosin capsule is not recommended [see CLINICAL PHARMACOLOGY (12.3)]. 2.2 Dosage Adjustment in Special Populations Renal impairment: Silodosin capsule is contraindicated in patients with severe renal impairment (CCr < 30 mL/min). In patients with moderate renal impairment (CCr 30 to 50 mL/min), the dose should be reduced to 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50 to 80 mL/min) [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.2), USE IN SPECIFIC POPULATIONS (8.6), and CLINICAL PHARMACOLOGY (12.3 ) ]. Hepatic impairment: Silodosin capsule has not been studied in patients with severe hepatic impairment (Child-Pugh score ≥ 10) and is therefore contraindicated in these patients. No dosage adjustment is needed in patients with mild or moderate hepatic impairment [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.3), USE IN SPECIFIC POPULATIONS (8.7), and CLINICAL PHARMACOLOGY (12.3 ) ].

4 CONTRAINDICATIONS Severe renal impairment (CCr <30 mL/min) Severe hepatic impairment (Child-Pugh score ≥10) Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) [see DRUG INTERACTIONS (7.1)] Patients with a history of hypersensitivity to silodosin or any of the ingredients of silodosin capsules [see ADVERSE REACTIONS (6.2) and DESCRIPTION (11)] Patients with severe renal impairment [Creatinine Clearance (CCr <30 mL/min)]. (4) Patients with severe hepatic impairment (Child-Pugh score ≥ 10). (4) Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir). (4) Patients with a history of hypersensitivity to silodosin or any of the ingredients of silodosin capsules. (4)

5 WARNINGS AND PRECAUTIONS Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning silodosin capsules treatment. (5.1) In patients with moderate renal impairment, silodosin capsules dose should be reduced to 4 mg once daily. (5.2) Silodosin capsules should not be used in combination with other alpha-blockers. (5.5) Examine patients thought to have BPH prior to starting therapy with silodosin capsules to rule out the presence of carcinoma of the prostate. (5.6) Inform patients planning cataract surgery to notify their ophthalmologist that they are taking silodosin capsules because of the possibility of Intraoperative Floppy Iris Syndrome (IFIS). (5.7) 5.1 Orthostatic Effects Postural hypotension, with or without symptoms (e.g., dizziness) may develop when beginning silodosin capsules treatment. As with other alpha-blockers, there is potential for syncope. Patients should be cautioned about driving, operating machinery, or performing hazardous tasks when initiating therapy [see ADVERSE REACTIONS (6), USE IN SPECIFIC POPULATIONS (8.5), CLINICAL PHARMACOLOGY (12.2), and PATIENT COUNSELING INFORMATION (17)]. 5.2 Renal Impairment In a clinical pharmacology study, plasma concentrations (AUC and C max ) of silodosin were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal function, while half-lives of silodosin doubled in duration. The dose of silodosin capsules should be reduced to 4 mg in patients with moderate renal impairment. Exercise caution and monitor such patients for adverse events [see USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)] . Silodosin capsules are contraindicated in patients with severe renal impairment [see CONTRAINDICATIONS (4)] . 5.3 Hepatic Impairment Silodosin capsule has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients [see CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)] . 5.4 Pharmacokinetic Drug-Drug Interactions In a drug interaction study, co-administration of a single 8 mg dose of silodosin capsules with 400 mg ketoconazole, a strong CYP3A4 inhibitor, caused a 3.8-fold increase in maximum plasma silodosin concentrations and 3.2-fold increase in silodosin exposure (i.e., AUC). Concomitant use of ketoconazole or other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) is therefore contraindicated [see DRUG INTERACTIONS (7.1)] . 5.5 Pharmacodynamic Drug-Drug Interactions The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin capsules should not be used in combination with other alpha-blockers [see DRUG INTERACTIONS (7.3)]. A specific pharmacodynamic interaction study between silodosin and antihypertensive agents has not been performed. However, patients in the Phase 3 clinical studies taking concomitant antihypertensive medications with silodosin capsules did not experience a significant increase in the incidence of syncope, dizziness, or orthostasis. Nevertheless, exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events [see ADVERSE REACTIONS (6.1) and DRUG INTERACTIONS (7.6)]. Caution is also advised when alpha-adrenergic blocking agents including silodosin capsules are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [see DRUG INTERACTIONS (7.5)]. 5.6 Carcinoma of the Prostate Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Therefore, patients thought to have BPH should be examined prior to starting therapy with silodosin capsules to rule out the presence of carcinoma of the prostate. 5.7 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients on alpha-1 blockers or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents; progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs; and potential prolapse of the iris toward the phacoemulsification incisions. Patients planning cataract surgery should be told to inform their ophthalmologist that they are taking silodosin capsules [see ADVERSE REACTIONS (6.1)]. 5.8 Laboratory Test Interactions No laboratory test interactions were observed during clinical evaluations. Treatment with silodosin capsules for up to 52 weeks had no significant effect on prostate-specific antigen (PSA).

7 DRUG INTERACTIONS Strong P-glycoprotein inhibitors (e.g., cyclosporine): Co-administration may increase plasma silodosin concentration. Concomitant use is not recommended. (7.2) Alpha-blockers: Interactions involving concomitant use have not been determined. However, interactions are expected and concomitant use is not recommended. (7.3) Concomitant use of PDE5 inhibitors with alpha-blockers including silodosin can potentially cause symptomatic hypotension. (5.5) (7.5) 7.1 Moderate and Strong CYP3A4 Inhibitors In a clinical metabolic inhibition study, a 3.8-fold increase in silodosin maximum plasma concentrations and 3.2-fold increase in silodosin exposure were observed with concurrent administration of a strong CYP3A4 inhibitor, 400 mg ketoconazole. Use of strong CYP3A4 inhibitors such as itraconazole or ritonavir may cause plasma concentrations of silodosin to increase. Concomitant administration of strong CYP3A4 inhibitors and silodosin capsule is contraindicated [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.4) and CLINICAL PHARMACOLOGY (12.3)] . The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated. Concomitant administration with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may increase concentration of silodosin capsules. Exercise caution and monitor patients for adverse events when co-administering silodosin capsules with moderate CYP3A4 inhibitors. 7.2 Strong P-glycoprotein (P-gp) Inhibitors In vitro studies indicated that silodosin is a P-gp substrate. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin capsule is therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine [see CLINICAL PHARMACOLOGY (12.3)]. 7.3 Alpha-Blockers The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin capsules should not be used in combination with other alpha-blockers [see WARNINGS AND PRECAUTIONS (5.5)]. 7.4 Digoxin The effect of co-administration of silodosin capsules and digoxin 0.25 mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of silodosin capsules and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required. 7.5 PDE5 Inhibitors Co-administration of silodosin capsules with a single dose of 100 mg sildenafil or 20 mg tadalafil was evaluated in a placebo-controlled clinical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital signs were monitored in the 12-hour period following concomitant dosing. During this period, the total number of positive orthostatic test results was greater in the group receiving silodosin capsules plus a PDE5 inhibitor compared with silodosin capsules alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin capsules with a PDE5 inhibitor. 7.6 Other Concomitant Drug Therapy Antihypertensives The pharmacodynamic interactions between silodosin and antihypertensives have not been rigorously investigated in a clinical study. However, approximately one-third of the patients in clinical studies used concomitant antihypertensive medications with silodosin capsules. The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general silodosin population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively). Exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events [see WARNINGS AND PRECAUTIONS (5.5)]. Metabolic Interactions In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems. 7.7 Food Interactions The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (C max ) by approximately 18 to 43% and exposure (AUC) by 4 to 49% across three different studies. Safety and efficacy clinical trials for silodosin capsules were always conducted in the presence of food intake. Patients should be instructed to take silodosin with a meal to reduce risk of adverse events [see CLINICAL PHARMACOLOGY (12.3)] .

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 2%) are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. (6) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In U.S. clinical trials, 897 patients with BPH were exposed to 8 mg silodosin capsules daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 to 87 years of age, and predominantly Caucasian. Of these patients, 42.8% were 65 years of age or older and 10.7% were 75 years of age or older. In double-blind, placebo controlled, 12-week clinical trials, 466 patients were administered silodosin capsules and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of silodosin capsules treated patients (36.8% for placebo treated). The majority (72.1%) of adverse reactions for the silodosin capsules treated patients (59.8% for placebo treated) were qualified by the investigator as mild. A total of 6.4% of silodosin capsules treated patients (2.2% for placebo treated) discontinued therapy due to an adverse reaction (treatment-emergent), the most common reaction being retrograde ejaculation (2.8%) for silodosin capsules treated patients. Retrograde ejaculation is reversible upon discontinuation of treatment. Adverse Reactions observed in at least 2% of patients: The incidence of treatment-emergent adverse reactions listed in the following table were derived from two 12-week, multicenter, double-blind, placebo-controlled clinical studies of silodosin capsules 8 mg daily in BPH patients. Adverse reactions that occurred in at least 2% of patients treated with silodosin capsules and more frequently than with placebo are shown in Table 1. Table 1: Adverse Reactions Occurring in ≥2% of Patients in 12-week, Placebo-Controlled Clinical Trials Adverse Reactions Silodosin Capsules N = 466 n (%) Placebo N = 457 n (%) Retrograde Ejaculation 131 (28.1) 4 (0.9) Dizziness 15 (3.2) 5 (1.1) Diarrhea 12 (2.6) 6 (1.3) Orthostatic Hypotension 12 (2.6) 7 (1.5) Headache 11 (2.4) 4 (0.9) Nasopharyngitis 11 (2.4) 10 (2.2) Nasal Congestion 10 (2.1) 1 (0.2) In the two 12-week, placebo-controlled clinical trials, the following adverse events were reported by between 1% and 2% of patients receiving silodosin capsules and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia, and rhinorrhea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the silodosin capsules treatment group. In a 9-month open-label safety study of silodosin capsules, one case of Intraoperative Floppy Iris Syndrome (IFIS) was reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of silodosin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Skin and subcutaneous tissue disorders: toxic skin eruption, purpura, skin rash, pruritus, and urticaria Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values Immune system disorders: allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in serious outcomes

8.1 Pregnancy Risk Summary Silodosin capsule is not indicated for use in females.