Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Recordati Ireland Ltd., Raheens East, Ringaskiddy Co. Cork, Ireland
Pharmacotherapeutic group: Urologicals, alpha-adrenoreceptor antagonists
ATC code: G04CA04
Silodosin is highly selective for α1A-adrenoreceptors that are primarily located in the human prostate, bladder base, bladder neck, prostatic capsule and prostatic urethra. Blockade of these α1A-adrenoreceptors causes smooth muscle in these tissues to relax, thus decreasing bladder outlet resistance, without affecting detrusor smooth muscle contractility. This causes an improvement of both storage (irritative) and voiding (obstructive) symptoms (Lower urinary tract symptoms, LUTS) associated with benign prostatic hyperplasia. Silodosin has a substantially lower affinity for the α1B-adrenoreceptors that are primarily located in the cardiovascular system. It has been demonstrated in vitro that the α1A:α1B binding ratio of silodosin (162:1) is extremely high.
In a Phase II dose-finding, double-blind, placebo-controlled clinical study with silodosin 4 or 8 mg once daily, a greater improvement in American Urologic Association (AUA) symptom index score was observed with silodosin 8 mg (-6.8±5.8, n=90; p=0.0018) and silodosin 4 mg (-5.7±5.5, n=88; p=0.0355) as compared to placebo (-4.0±5.5, n=83).
Over 800 patients with moderate to severe symptoms of BPH (International Prostate Symptom Score, IPSS, baseline value ≥13) received silodosin 8 mg once daily in two Phase III placebo-controlled clinical studies conducted in the United States and in one placebo- and active-controlled clinical study conducted in Europe. In all studies, patients who did not respond to placebo during a 4-week placebo run-in phase were randomised to receive the study treatment. In all studies, patients treated with silodosin had a greater decrease in both storage (irritative) and voiding (obstructive) symptoms of BPH as compared to placebo as assessed after 12 weeks of treatment.
Data observed in the Intent-to-treat populations of each study are shown below:
| Study | Treatment arm | No. of patients | IPSS Total score | IPSS Irritative symptoms | IPSS Obstructive symptoms | ||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline value (±SD) | Change from baseline | Difference (95% CI) vs placebo | Change from baseline | Difference (95% CI) vs placebo | Change from baseline | Difference (95% CI) vs placebo | |||
| US-1 | Silodosin | 233 | 22±5 | -6,5 | -2,8* (–3,9, -1,7) | -2,3 | -0,9* (–1,4, -0,4) | -4,2 | -1,9* (–2,6, -1,2) |
| Placebo | 228 | 21±5 | -3,6 | -1,4 | -2,2 | ||||
| US-2 | Silodosin | 233 | 21±5 | -6,3 | -2,9* (–4,0, -1,8) | -2,4 | -1,0* (–1,5, -0,6) | -3,9 | -1,8* (–2,5, -1,1) |
| Placebo | 229 | 21±5 | -3,4 | -1,3 | -2,1 | ||||
| /Europe | Silodosin | 371 | 19±4 | -7,0 | -2,3* (–3,2, -1,4) | -2,5 | -0,7° (–1,1, -0,2) | -4,5 | -1,7* (–2,2, -1,1) |
| Tamsulosin | 376 | 19±4 | -6,7 | -2,0* (–2,9, -1,1) | -2,4 | -0,6° (–1,1, -0,2) | -4,2 | -1,4* (–2,0, -0,8) | |
| Placebo | 185 | 19±4 | -4,7 | -1,8 | -2,9 | ||||
* p<0.001 vs Placebo; °p=0.002 vs Placebo
In the active-controlled clinical study conducted in Europe, silodosin 8 mg once daily was shown to be non inferior to tamsulosin 0.4 mg once daily: the adjusted mean difference (95% CI) in the IPSS Total Score between treatments in the per-protocol population was 0.4 (-0.4 to 1.1). The responder rate (i.e. improvement in the IPSS total score by at least 25%) was significantly higher in the silodosin (68%) and tamsulosin group (65%), as compared to placebo (53%).
In the long-term open-label extension phase of these controlled studies, in which patients received silodosin for up to 1 year, the symptom improvement induced by silodosin at week 12 of treatment was maintained over 1 year.
In a Phase IV clinical trial performed in Europe, with a mean baseline IPSS total score of 18.9 points, 77.1%were responders to silodosin (as assessed by a change from baseline in the IPSS total score of at least 25%). Approximately half of the patients reported an improvement in the most bothersome symptoms complained at baseline by the patients (i.e. nocturia, frequency, decreased stream, urgency, terminal dribbling and incomplete emptying), as assessed by the ICS-male questionnaire.
No significant reduction in supine blood pressure was observed in all clinical studies conducted with silodosin.
Silodosin 8 mg and 24 mg daily had no statistically significant effect on ECG intervals or cardiac repolarisation relative to placebo.
The European Medicines Agency has waived the obligation to submit the results of studies with Urorec in all subsets of the paediatric population in BPH (see section 4.2 for information on paediatric use).
The pharmacokinetics of silodosin and its main metabolites have been evaluated in adult male subjects with and without BPH after single and multiple administrations with doses ranging from 0.1 mg to 48 mg per day. The pharmacokinetics of silodosin is linear throughout this dose range.
The exposure to the main metabolite in plasma, silodosin glucuronide (KMD-3213G), at steady-state is about 3-fold that of the parent substance. Silodosin and its glucuronide reach steady-state after 3 days and 5 days of treatment, respectively.
Silodosin administered orally is well absorbed and absorption is dose proportional. The absolute bioavailability is approximately 32%.
An in vitro study with Caco-2 cells showed that silodosin is a substrate for P-glycoprotein.
Food decreases Cmax by approximately 30%, increases tmax by approximately 1 hour and has little effect on AUC.
In healthy male subjects of the target age range (n=16, mean age 55±8 years) after once-a-day oral administration of 8 mg immediately after breakfast for 7 days, the following pharmacokinetic parameters were obtained: Cmax 87±51 ng/ml (sd), tmax 2.5 hours (range 1.0-3.0), AUC 433±286 ng•h/ml.
Silodosin has a volume of distribution of 0.81 l/kg and is 96.6% bound to plasma proteins. It does not distribute into blood cells.
Protein binding of silodosin glucuronide is 91%.
Silodosin undergoes extensive metabolism through glucuronidation (UGT2B7), alcohol and aldehyde dehydrogenase and oxidative pathways, mainly CYP3A4. The main metabolite in plasma, the glucuronide conjugate of silodosin (KMD-3213G), that has been shown to be active in vitro, has an extended half-life (approximately 24 hours) and reaches plasma concentrations approximately four times higher than those of silodosin. In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.
Following oral administration of 14C-labelled silodosin, the recovery of radioactivity after 7 days was approximately 33.5% in urine and 54.9% in faeces. Body clearance of silodosin was approximately 0.28 l/h/kg. Silodosin is excreted mainly as metabolites, very low amounts of unchanged drug are recovered in urine. The terminal half-life of parent drug and its glucuronide is approximately 11 hours and 18 hours, respectively.
Exposure to silodosin and its main metabolites does not change significantly with age, even in subjects of age over 75 years.
Silodosin has not been evaluated in patients less than 18 years of age.
In a single-dose study, the pharmacokinetics of silodosin was not altered in nine patients with from this study should be interpreted with caution, since enrolled patients had normal biochemistry values, indicating normal metabolic function, and they were classified as having moderate liver impairment based on ascites and hepatic encephalopathy.
The pharmacokinetics of silodosin in patients with severe hepatic impairment has not been studied.
In a single-dose study, exposure to silodosin (unbound) in subjects with mild (n=8) and moderate renal impairment (n=8) resulted, on average, in an increase of Cmax (1.6-fold) and AUC (1.7-fold) relative to subjects with normal renal function (n=8). In subjects with severe renal impairment (n=5) increase of exposure was 2.2-fold for Cmax and 3.7-fold for AUC. Exposure to the main metabolites, silodosin glucuronide and KMD3293, was also increased.
Plasma level monitoring in a Phase III clinical study showed that levels of total silodosin after 4 weeks of treatment did not change in patients with mild impairment (n=70), compared to patients with normal renal function (n=155), while the levels were doubled on average in patients with moderate impairment (n=7).
A review of safety data of patients enrolled in all clinical studies does not indicate that mild renal impairment (n=487) poses an additional safety risk during silodosin therapy (such as an increase in dizziness or orthostatic hypotension) as compared to patients with normal renal function (n=955). Accordingly, no dose adjustment is required in patients with mild renal impairment. Since only limited experience exists in patients with moderate renal impairment (n=35), a lower starting dose of 4 mg is recommended. In patients with severe renal impairment administration of Urorec is not recommended.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, carcinogenic, mutagenic and teratogenic potential. Effects in animals (affecting the thyroid gland in rodents) were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
In male rats, decreased fertility was observed from exposures which were approximately twice the exposure at the maximum recommended human dose. The observed effect was reversible.
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