silodosin 4 MG Oral Capsule [Rapaflo]

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.

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 )] .

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 capsule dose should be reduced to 4mg 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 capsules 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).

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 )]

CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Orthostatic Effects A test for postural hypotension was conducted 2 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 capsules N=466 n (%) Placebo N=457 n (%) 1 Minute After Standing Negative 459 (98.7) 454 (99.6) Positive 6 (1.3) 2 (0.4) 3 Minutes After Standing Negative 456 (98.1) 454 (99.6) Positive 9 (1.9) 2 (0.4) Cardiac Electrophysiology The effect of silodosin capsules 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 to 45 years. Subjects received either silodosin capsules 8 mg, silodosin capsules 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 capsules 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 capsules 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 Torsade de Pointes in the post-marketing experience with silodosin outside the United States. 12.3 Pharmacokinetics The pharmacokinetics of silodosin have been evaluated in adult male subjects with doses ranging from 0.1 mg to 24 mg per day. The pharmacokinetics of silodosin are linear throughout this dosage range. Absorption The pharmacokinetic characteristics of silodosin 8 mg once daily were determined in a multi-dose, open-label, 7‑day pharmacokinetic study completed in 19 healthy, target-aged (≥ 45 years of age) male subjects. Table 3 presents the steady state pharmacokinetics of this study. Table 3 Mean (±SD) Steady State Pharmacokinetic Parameters in Healthy Males Following Silodosin 8 mg Once Daily with Food C max (ng/mL) t max (hours) t 1/2 (hours) AUC ss (ng•hr/mL) 61.6 ± 27.54 2.6 ± 0.90 13.3 ± 8.07 373.4 ± 164.94 C max = maximum concentration, t max = time to reach C max , t 1/2 = elimination half-life, AUC ss = steady state area under the concentration-time curve Figure 1 Mean (±SD) Silodosin Steady State Plasma Concentration-Time Profile in Healthy Target-Aged Subjects Following Silodosin 8 mg Once Daily with Food The absolute bioavailability is approximately 32%. Food Effect The maximum effect of food (i.e., co‑administration with a high fat, high calorie meal) on the PK of silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin C max by approximately 18% to 43% and AUC by 4% to 49% across three different studies. In a single-center, open-label, single-dose, randomized, two-period crossover study in twenty healthy male subjects age 21 to 43 years under fed conditions, a study was conducted to evaluate the relative bioavailability of the contents of an 8 mg capsule (size #1) of silodosin sprinkled on applesauce compared to the product administered as an intact capsule. Based on AUC 0–24 and C max , silodosin administered by sprinkling the contents of a silodosin capsule onto a tablespoonful of applesauce was found to be bioequivalent to administering the capsule whole. Distribution Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound. Elimination Metabolism Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD‑3213G) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Co‑administration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, fluconazole) may potentially increase exposure to silodosin. KMD‑3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four times greater than that of silodosin. The second major metabolite (KMD‑3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin. KMD‑3293 is not expected to contribute significantly to the overall pharmacologic activity of silodosin capsules. Excretion Following oral administration of 14 C‑labeled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in urine and 54.9% in feces. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour. Special Populations Race No clinical studies specifically investigating the effects of race have been performed. Geriatric In a study comparing 12 geriatric males (mean age 69 years) and 9 young males (mean age 24 years), the exposure (AUC) and elimination half-life of silodosin were approximately 15% and 20%, respectively, greater in geriatric than young subjects. No difference in the C max of silodosin was observed [see USE IN SPECIFIC POPULATIONS (8.5) ]. Pediatric Silodosin capsules has not been evaluated in patients less than 18 years of age. Renal Impairment In a study with six subjects with moderate renal impairment, the total silodosin (bound and unbound) AUC, C max , and elimination half-life were 3.2-, 3.1-, and 2‑fold higher, respectively, compared to seven subjects with normal renal function. The unbound silodosin AUC and C max were 2.0- and 1.5‑fold higher, respectively, in subjects with moderate renal impairment compared to the normal controls. In controlled and uncontrolled clinical studies, the incidence of orthostatic hypotension and dizziness was greater in subjects with moderate renal impairment treated with 8 mg silodosin capsules daily than in subjects with normal or mildly impaired renal function [see CONTRAINDICATIONS (4) , WARNINGS AND PRECAUTIONS (5.2) and USE IN SPECIFIC POPULATIONS (8.6) ]. 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 pharmacokinetic disposition of silodosin was not significantly altered in the patients with moderate hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of silodosin in patients with severe hepatic impairment have not been studied [see CONTRAINDICATIONS (4) , WARNINGS AND PRECAUTIONS (5.3) and USE IN SPECIFIC POPULATIONS (8.7) ]. D