Silodosin
Silodosin Prescribing Information
Silodosin, a selective alpha‑1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH)
Two 12‑week, randomized, double-blind, placebo-controlled, multicenter studies were conducted with 8 mg daily of silodosin. In these two studies, 923 patients [mean age 64.6 years; Caucasian (89.3%), Hispanic (4.9%), Black (3.9%), Asian (1.2%), Other (0.8%)] were randomized and 466 patients received silodosin capsules 8 mg daily. The two studies were identical in design except for the inclusion of pharmacokinetic sampling in Study 1. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure.
Mean changes from baseline to last assessment (Week 12) in total IPSS score were statistically significantly greater for groups treated with silodosin than those treated with placebo in both studies (Table 4 and Figures 2 and 3).
Total Symptom Score | Study 1 | Study 2 | ||||
Silodosin capsules 8 mg (n = 233) | Placebo (n = 228) | p‑value | Silodosin capsules 8 mg (n = 233) | Placebo (n = 229) | p‑value | |
| Baseline | 21.5 (5.38) | 21.4 (4.91) | 21.2 (4.88) | 21.2 (4.92) | ||
| Week 12 / LOCF Change from Baseline | -6.5 (6.73) | -3.6 (5.85) | < 0.0001 | -6.3 (6.54) | -3.4 (5.83) | < 0.0001 |
| LOCF – Last observation carried forward for those not completing 12 weeks of treatment. | ||||||
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Mean IPSS total score for silodosin capsules once daily groups showed a decrease starting at the first scheduled observation and remained decreased through the 12 weeks of treatment in both studies.
Silodosin capsules produced statistically significant increases in maximum urinary flow rates from baseline to last assessment (Week 12) versus placebo in both studies (Table 5 and Figures 4 and 5). Mean peak flow rate increased starting at the first scheduled observation at Day 1 and remained greater than the baseline flow rate through the 12 weeks of treatment for both studies.
Mean Maximum Flow Rate (mL/sec) | Study 1 | Study 2 | ||||
Silodosin capsule 8 mg (n = 233) | Placebo (n = 228) | p‑value | Silodosin capsule 8 mg (n = 233) | Placebo (n = 229) | p‑value | |
| Baseline | 9.0 (2.60) | 9.0 (2.85) | 8.4 (2.48) | 8.7 (2.67) | ||
| Week 12 / LOCF Change from Baseline | 2.2 (4.31) | 1.2 (3.81) | 0.0060 | 2.9 (4.53) | 1.9 (4.82) | 0.0431 |
| LOCF – Last observation carried forward for those not completing 12 weeks of treatment. | ||||||
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Note – The first Qmaxassessments at Day 1 were taken 2 to 6 hours after patients received the first dose of double-blind medication.
Note – Measurements at each visit were scheduled 2 to 6 hours after dosing (approximate peak plasma silodosin concentration).
B- Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Note – The first Qmaxassessments at Day 1 were taken 2 to 6 hours after patients received the first dose of double-blind medication.
Note – Measurements at each visit were scheduled 2 to 6 hours after dosing (approximate peak plasma silodosin concentration).
- 8mg capsules taken orally once daily with a meal. ()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)]. - 4mg capsules taken orally once daily with a meal for those with moderate renal impairment [Creatinine Clearance (CCr) 30 to 50mL/min]. ()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 30-50 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)
[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 ≥ 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)].
The 4 mg capsules are white opaque cap and body, size "3". The cap is imprinted in black ink with "479". The body is imprinted in black ink with '4'.
The 8 mg capsules are white opaque cap and body, size "1". The cap is imprinted in black ink with "480". The body is imprinted in black ink with '8'.
- Renal impairment: Dose adjustment in moderate disease, (). Contraindicated in severe renal disease. (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 30-50 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)
[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 ≥ 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 in silodosin capsules[see ADVERSE REACTIONS (6.2)AND DESCRIPTION (11)]
- 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.
- Hepatic impairment: Contraindicated in severe disease. ()
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 in silodosin capsules[see ADVERSE REACTIONS (6.2)AND DESCRIPTION (11)]
- 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.
- 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]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.
- Patients with a history of hypersensitivity to silodosin or any of the ingredients in silodosin capsules[seeAND6.2 Post-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 urticariaHepatobiliary disorders:
jaundice, impaired hepatic function associated with increased transaminase valuesImmune system disorders:
allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in serious outcomes.]11 DESCRIPTIONSilodosin capsules is 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 C25H32F3N3O4with 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, magnesium stearate, pregelatinized starch and sodium lauryl sulfate. The size #1 hard gelatin capsules contain gelatin, sodium lauryl sulfate and titanium dioxide. The Capsules are imprinted with black ink containing shellac, propylene glycol, ammonia solution- concentrated, black iron oxide and potassium hydroxide.
Each Silodosin 4 mg capsule for oral administration contains 4 mg silodosin, and the following inactive ingredients: mannitol, magnesium stearate, pregelatinized starch and sodium lauryl sulfate. The size #3 hard gelatin capsules contain gelatin, sodium lauryl sulfate and titanium dioxide. The Capsules are imprinted with black ink Containing shellac, propylene glycol, ammonia solution-concentrated, black iron oxide and potassium hydroxide.
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- Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning silodosin capsules treatment. ()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)]. - In patients with moderate renal impairment, silodosin capsule dose should be reduced to 4mg once daily. ()5.2 Renal Impairment
In a clinical pharmacology study, plasma concentrations (AUC and Cmax) 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)]. - Silodosin capsules should not be used in combination with other alpha-blockers. ()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)]. - 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 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.
- 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 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)].