Silodosin

DOSAGE AND ADMINISTRATION, Dosing Information (2.1) 12/2012 CONTRAINDICATIONS (4) 01/2013

1 INDICATIONS AND USAGE Silodosin capsules, 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 capsules are not indicated for the treatment of hypertension. Silodosin capsules, an alpha-1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin capsules are 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 mL/min -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 capsules are contraindicated in patients with severe renal impairment (CCr less than 30 mL/min). In patients with moderate renal impairment (CCr 30 mL/min -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 mL/min - 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 capsules has not been studied in patients with severe hepatic impairment (Child-Pugh score greater than or equal to 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 )].

3 DOSAGE FORMS AND STRENGTHS The 8 mg capsules are size ‘1’ capsules with white opaque hard gelatin cap imprinted with “SIL” and white opaque hard gelatin body imprinted with “8 mg” in black ink containing white to off‐white powder. The 4 mg capsules are size ‘3’ capsules with white opaque hard gelatin cap imprinted with “SIL” and white opaque hard gelatin body imprinted with “4 mg” in black ink containing white to off‐white powder. Capsules: 8 mg and 4 mg. ( 3 )

4 CONTRAINDICATIONS Severe renal impairment (CCr less than 30 mL/min) Severe hepatic impairment (Child-Pugh score greater than or equal to 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 less than 30 mL/min)]. ( 4 ) Patients with severe hepatic impairment (Child-Pugh score greater than 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 )

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than 2%) are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA, Inc., at 1-855-664-7744 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 greater than or equal to 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

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 capsules 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 capsules 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 capsules 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 Interactio …

8 USE IN SPECIFIC POPULATIONS Renal impairment: Dose adjustment in moderate disease (2.2). Contraindicatedin severe renal disease. (4) Hepatic impairment: Contraindicated in severe disease. (4) 8.1 Pregnancy Pregnancy Category B. Silodosin capsule is not indicated for use in women. An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13 to 25 times the maximum recommended human exposure or MRHE of silodosin via AUC). No statistically significant teratogenicity was observed at this dose. Silodosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated silodosin, which is present in human serum at approximately 4 times the level of circulating silodosin and which has similar pharmacological activity to silodosin. No effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day. 8.4 Pediatric Use Silodosin capsules are not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In double-blind, placebo-controlled, 12-week clinical studies of silodosin capsules, 259 (55.6%) were under 65 years of age, 207 (44.4%) patients were 65 years of age and over, while 60 (12.9%) patients were 75 years of age and over. Orthostatic hypotension was reported in 2.3% of silodosin capsules patients <65 years of age (1.2% for placebo), 2.9% of silodosin capsules patients ≥65 years of age (1.9% for placebo), and 5% of patients ≥75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients [see Clinical Pharmacology (12.3)] . 8.6 Renal Impairment The effect of renal impairment on silodosin pharmacokinetics was evaluated in a single dose study of six male patients with moderate renal impairment and seven male subjects with normal renal function. Plasma concentrations of silodosin were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal function. Silodosin capsules should be reduced to 4 mg per day in patients with moderate renal impairment. Exercise caution and monitor patients for adverse events. Silodosin capsule has not been studied in patients with severe renal impairment. Silodosin capsules are contraindicated in patients with severe renal impairment [ see Contraindications (4), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment In a study comparing nine male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), to nine healthy male subjects, the single dose pharmacokinetics of silodosin were not significantly altered in patients with hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Silodosin capsule has not been studied in patients with severe hepatic impairment. Silodosin capsules are contraindicated in patients with severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] .

12.1 Mechanism of Action Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms. An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 adrenoreceptors (alpha-1A, alpha-1B, and alpha-1D) was conducted. The results of the study demonstrated that silodosin binds with high affinity to the alpha-1A subtype.

11 DESCRIPTION Silodosin capsules, a selective antagonist of alpha-1 adrenoreceptors. The chemical name of silodosin is 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2 (2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-1 H -indole-7-carboxamide and the molecular formula is C 25 H 32 F 3 N 3 O 4 with a molecular weight of 495.53. The structural formula of silodosin is: Silodosin is a white to pale yellowish white powder that melts at approximately 105 to 109°C. It is freely soluble in acetic acid and in absolute alcohol, and insoluble in water. Each silodosin 8 mg capsule for oral administration contains 8 mg silodosin, and the following inactive ingredients: mannitol, pregelatinized starch, sodium lauryl sulfate and sodium stearyl fumarate. The size #1 hard gelatin capsules contain FD & C Blue 1, FD & C Red 3, FD & C Red 40, gelatin and titanium dioxide. The capsules are printed with edible ink containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. Each silodosin 4 mg capsule for oral administration contains 4 mg silodosin, and the following inactive ingredients: mannitol, pregelatinized starch, sodium lauryl sulfate and sodium stearyl fumarate. The size #3 hard gelatin capsules contain gelatin and titanium dioxide. The capsules are printed with edible ink containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. structure

10 OVERDOSAGE Silodosin capsules was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was postural hypotension. Should overdose of silodosin capsules lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by maintaining the patient in the supine position. If this measure is inadequate, administration of intravenous fluid should be considered. If necessary, vasopressors could be used, and renal function should be monitored and supported as needed. Dialysis is unlikely to be of significant benefit since silodosin is highly (97%) protein bound.

16 HOW SUPPLIED/STORAGE AND HANDLING Silodosin Capsules, 4 mg are White cap / White body size ‘3’ hard gelatin capsules imprinted with ‘H’ on cap and ‘S1’ on body, filled with white to off white powder. They are supplied as follows: White Colored Bottles of 30 Capsules NDC 31722-635-30 Amber Colored Bottles of 30 Capsules NDC 31722-635-31 White Colored Bottles of 90 Capsules NDC 31722-635-90 Amber Colored Bottles of 90 Capsules NDC 31722-635-91 Bottles of 30 and 90 capsules are supplied with child-resistant closures. Silodosin Capsules, 8 mg are White cap / White body size ‘1’ hard gelatin capsules imprinted with ‘H’ on cap and ‘S2’ on body, filled with white to off white powder. They are supplied as follows: White Colored Bottles of 30 Capsules NDC 31722-636-30 Amber Colored Bottles of 30 Capsules NDC 31722-636-31 White Colored Bottles of 90 Capsules NDC 31722-636-90 Amber Colored Bottles of 90 Capsules NDC 31722-636-91 Bottles of 30 and 90 capsules are supplied with child-resistant closures. Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Keep out of reach of children.