Flosin

1 INDICATIONS AND USAGE Silodosin capsules, 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 ) 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.

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 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 mL/min 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 mL/min 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 )] .

12.2 Pharmacodynamics Orthostatic Effects A test for postural hypotension was conducted 2 hours to 6 hours after the first dose in the two 12-week, double-blind, placebo-controlled clinical studies. After the patient had been at rest in a supine position for 5 minutes, the patient was asked to stand. Blood pressure and heart rate were assessed at 1 minute and 3 minutes after standing. A positive result was defined as a > 30 mmHg decrease in systolic blood pressure, or a > 20 mmHg decrease in diastolic blood pressure, or a > 20 bpm increase in heart rate [see WARNINGS AND PRECAUTIONS ( 5.1 ) ]. Table 2: Summary of Orthostatic Test Results in 12-week, Placebo-Controlled Clinical Trials Time of Measurement Test Result Silodosin N=466 n (%) Placebo N=457 n (%) 1 Minute After Standing Negative Positive 459 (98.7) 6 (1.3) 454 (99.6) 2 (0.4) 3 Minutes After Standing Negative Positive 456 (98.1) 9 (1.9) 454 (99.6) 2 (0.4) Cardiac Electrophysiology The effect of silodosin on QT interval was evaluated in a double-blind, randomized, active- (moxifloxacin) and placebo-controlled, parallel-group study in 189 healthy male subjects aged 18 years to 45 years. Subjects received either silodosin 8 mg, silodosin 24 mg, or placebo once daily for five days, or a single dose of moxifloxacin 400 mg on Day 5 only. The 24 mg dose of silodosin was selected to achieve blood levels of silodosin that may be seen in a "worst-case" scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors) [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.3 ) and CLINICAL PHARMACOLOGY ( 12.3 )] . QT interval was measured during a 24-hour period following dosing on Day 5 (at silodosin steady state). Silodosin was not associated with an increase in individual corrected (QTcI) QT interval at any time during steady state measurement, while moxifloxacin, the active control, was associated with a maximum 9.59 msec increase in QTcI. There has been no signal of…

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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 years 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 and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of silodosin treated patients (36.8% for placebo treated). The majority (72.1%) of adverse reactions for the silodosin treated patients (59.8% for placebo treated) were qualified by the investigator as mild. A total of 6.4% of silodosin 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 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 8 mg daily in BPH patients.…

4 CONTRAINDICATIONS 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 ) 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 )]

5 WARNINGS AND PRECAUTIONS Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning silodosin treatment. ( 5.1 ) In patients with moderate renal impairment, silodosin dose should be reduced to 4 mg once daily. ( 5.2 ) Silodosin should not be used in combination with other alpha-blockers. ( 5.5 ) Examine patients thought to have BPH prior to starting therapy with silodosin 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 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 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 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 is contraindicated in patients with severe renal impairment [see CONTRAINDICATIONS ( 4 )]. 5.3 Hepatic Impairment Silodosin 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 (…

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 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. Exercise caution and monitor patients for adverse events when co-administering silodosin 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 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.…