Silodosin

Silodosin, a selective alpha‑1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) . Silodosin capsules is 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.

2 DOSAGE AND ADMINISTRATION 8mg capsules taken orally once daily with a meal. 4mg capsules taken orally once daily with a meal for those with moderate renal impairment [Creatinine Clearance (CCr) 30 to 50mL/min].

2.1Dosing 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 .

2.2Dosage 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 30-50 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 50-80 mL/min) . Hepatic impairment: Silodosin capsules 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 .

Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning silodosin capsules treatment. In patients with moderate renal impairment, silodosin capsule dose should be reduced to 4mg once daily. Silodosin capsules should not be used in combination with other alpha-blockers. Examine patients thought to have BPH prior to starting therapy with silodosin capsules to rule out the presence of carcinoma of the prostate. 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).

5.1Orthostatic 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 .

5.2Renal 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 . Silodosin capsules are contraindicated in patients with severe renal impairment .

5.3Hepatic Impairment Silodosin

capsules has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients .

5.4Pharmacokinetic 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 .

5.5Pharmacodynamic 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 . 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 . 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 .

5.6Carcinoma 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.

5.7Intraoperative 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 .

5.8Laboratory 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).

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) Patients with a history of hypersensitivity to silodosin or any of the ingredients in silodosin capsules Patients with severe renal impairment [Creatinine Clearance (CCr <30mL/min)]. Patients with severe hepatic impairment (Child-Pugh score >10). Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir).

Patients with a history of hypersensitivity to silodosin or any of the ingredients of silodosin capsules.

Renal impairment: Dose adjustment in moderate disease,. Contraindicated in severe renal disease. Hepatic impairment: Contraindicated in severe disease.

8.1Pregnancy Risk Summary Silodosin

capsules is not indicated for use in females.

8.2Lactation Silodosin

capsules is not indicated for use in females.

8.3Females and Males of Reproductive Potential Infertility

Males Possible effects on male fertility could be observed based on findings in rats at exposures that were at least two times higher than at the MRHD (based on AUC). These findings may be reversible, and the clinical relevance is unknown .

8.4Pediatric Use Silodosin

capsules is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.

8.5Geriatric Use In

double-blind, placebo-controlled, 12‑week clinical studies of silodosin capsules, 259 (55.6%) patients 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 5.0% of patients ≥ 75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients .

8.6Renal 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 capsules has not been studied in patients with severe renal impairment. Silodosin capsules is contraindicated in patients with severe renal impairment .

8.7Hepatic 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 capsules has not been studied in patients with severe hepatic impairment.

Silodosin capsules is contraindicated in patients with severe hepatic impairment .

Most common adverse reactions (incidence >2%) are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. To report SUSPECTED ADVERSE REACTIONS, contact Creekwood Pharmaceutical LLC. at 1-732-344-0220 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 4 Dizziness 15 5 Diarrhea 12 6 Orthostatic Hypotension 12 7 Headache 11 4 Nasopharyngitis 11 10 Nasal Congestion 10 1 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.

6.2Post-marketing 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.