DailyMed Label: Silodosin

DailyMed Label: Silodosin

2023

DailyMed Prescription

Silodosin

Silodosin

Lupin Pharmaceuticals, Inc.

NDC: 68180-740

NDC: 68180-741

NDC: 68180-740

NDC: 68180-741

NDC: 68180-740

NDC: 68180-740

NDC: 68180-741

NDC: 68180-741

Silodosin capsule is a selective antagonist of alpha-1 adrenoreceptors. The chemical name of silodosin is 1-(3-Hydroxypropyl)-5-[(2 R )-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°C to 109°C. It is freely soluble in acetic acid, freely soluble in alcohol, and insoluble in water. Each Silodosin 8 mg capsule for oral administration contains 8 mg silodosin, and the following inactive ingredients: magnesium stearate, mannitol and sodium lauryl sulfate. The size #1 hard gelatin capsules contain gelatin, sodium lauryl sulfate and titanium dioxide. The capsules are printed with edible ink containing FD&C Blue No. 2 Aluminum Lake, propylene glycol, shellac, titanium dioxide and yellow iron oxide. Each Silodosin 4 mg capsule for oral administration contains 4 mg silodosin, and the following inactive ingredients: magnesium stearate, mannitol and sodium lauryl sulfate. The size #3 hard gelatin capsules contain gelatin, sodium lauryl sulfate and titanium dioxide. The capsules are printed with edible ink containing propylene glycol, shellac and yellow iron oxide.

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 )

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 )

Capsules: 8 mg and 4 mg. ( 3 )

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 )

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 )

Most common adverse reactions (incidence ≥ 2%) are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. (

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 )

Renal impairment: Dose adjustment in moderate disease ( 2.2 ). Contraindicated in severe renal disease. ( 4 )   Hepatic impairment: Contraindicated in severe disease. ( 4 )

White, opaque, hard gelatin 8 mg capsules . Cap is imprinted with "LU" in green. Body is imprinted with "Q72" in green. 8 mg capsules are supplied in HDPE bottles of: 30 capsules (NDC 68180-741-06) 90 capsules (NDC 68180-741-09) 500 capsules (NDC 68180-741-02) Bottles of 30 and 90 capsules are supplied with child-resistant closures and bottle of 500 capsules is supplied with non-child-resistant closure. White, opaque, hard gelatin 4 mg capsules. Cap is imprinted with "LU" in gold. Body is imprinted with "Q71" in gold. 4 mg capsules are supplied in HDPE bottles of: 30 capsules (NDC 68180-740-06) 90 capsules (NDC 68180-740-09) 500 capsules (NDC 68180-740-02) Bottles of 30 and 90 capsules are supplied with child-resistant closures and bottle of 500 capsules is supplied with non-child-resistant closure. Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature.] Protect from light and moisture. Keep out of reach of children.

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.

In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day [about 8 times the exposure at the MRHD based on AUC of silodosin], an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of 150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known. In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about 9 times the exposure at the MRHD based on AUC of silodosin) and 400 mg/kg/day in females (about 72 times the exposure at the MRHD based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the exposure at the MRHD based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has similar pharmacological activity to silodosin. Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, mouse lymphoma assay, unscheduled DNA synthesis assay and the in vivo mouse micronucleus assay. A weakly positive response was obtained in two in vitro Chinese Hamster Lung (CHL) tests for chromosomal aberration assays at high, cytotoxic concentrations. Treatment of male rats with silodosin for 15 days resulted in decreased fertility at the high dose of 20 mg/kg/day (about 2 times the exposure at the MRHD based on AUC) which was reversible following a two week recovery period. No effect was observed at 6 mg/kg/day. The clinical relevance of this finding is not known. In a fertility study in female rats, the high dose of 20 mg/kg/day (about 1 to 4 times the exposure at the MRHD based on AUC) resulted in estrus cycle changes, but no effect on fertility. No effect on the estrus cycle was observed at 6 mg/kg/day. In a male rat fertility study, sperm viability and count were significantly lower after administration of 600 mg/kg/day (about 65 times the exposure at the MRHD based on AUC) for one month. Histopathological examination of infertile males revealed changes in the testes and epididymides at 200 mg/kg/day (about 30 times the exposure at the MRHD based on AUC).

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 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  8 mg (n = 233) Placebo (n = 228) p-value Silodosin  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 Figure 2: Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 1 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. Figure 3: Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 2 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 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 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  8 mg (n = 233) Placebo (n = 228) p-value Silodosin  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. Figure 4: Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 1 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 Qmax assessments at Day 1 were taken 2 hours to 6 hours after patients received the first dose of double-blind medication. Note – Measurements at each visit were scheduled 2 hours to 6 hours after dosing (approximate peak plasma silodosin concentration). Figure 5: Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 2 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 Qmax assessments at Day 1 were taken 2 hours to 6 hours after patients received the first dose of double-blind medication. Note – Measurements at each visit were scheduled 2 hours to 6 hours after dosing (approximate peak plasma silodosin concentration).

Silodosin Capsules, 4 mg X 30 capsules NDC 68180-740-06 Silodosin Capsules, 8 mg X 30 capsules NDC 68180-741-06