Silorun-D 4
Each hard gelatin capsule contains:
Silorun-D 8
Each hard gelatin capsule contains:
Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are found in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. As a result of blockage of these alpha-1 adrenoreceptors, smooth muscle in these tissues relaxes, resulting in an improvement in urine flow and reduction in benign prostatic hyperplasia 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.
The absolute bioavailability of silodosin is approximately 32%. The maximum effect of food (i.e., co-administration with a high fat, high calorie meal) on the pharmacokinetics of silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin Cmax by approximately 18-43% and AUC by 4-49% across three different studies. Silodosin is approximately 97% protein bound. 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), which has been shown in vitro to be active. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and is not expected to contribute significantly to the overall pharmacologic activity of silodosin. Following oral administration, silodosin is excreted approximately 33.5% in urine and 54.6% in feces. Mean half-life was 13.3 ± 8.07 hours. Glucuronide conjugate (KMD-3213G) has an extended half-life of approximately 24 hours. The elimination half-life was approximately 20% greater in the geriatric males compared with the younger males. In patients with moderate renal impairment, the total silodosin (bound and unbound) elimination half-life was approximately 2-fold higher than patients with normal renal function.
Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. It is not indicated for the treatment of hypertension.
Orthostatic Effects: Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning Silodosin 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.
Renal 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 should be reduced to 4 mg per day in patients with moderate renal impairment. Exercise caution and monitor patients for adverse events. Silodosin is contraindicated in patients with severe renal impairment.
Hepatic Impairment: No dosing adjustment is required in patients with mild or moderate hepatic impairment. Silodosin has not been studied in patients with severe hepatic impairment. Silodosin is contraindicated in patients with severe hepatic impairment.
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 to rule out the presence of carcinoma of the prostate.
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.
Effect on Ability to Drive and Use Machines: Postural hypotension, with or without symptoms (e.g., dizziness), may develop when beginning Silodosin 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.
Usage in Pregnancy and Lactation: Silodosin is not indicated for use in women. Silodosin was not teratogenic when administered to experimental animals. No effects on physical or behavioral development of offspring were observed when experimental animals were treated during pregnancy and lactation.
Usage in Pediatrics: Silodosin is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.
Orthostatic hypotension was reported in 2.3% of patients <65 years of age (1.2% for placebo), 2.9% of 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.
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 is contraindicated.
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. Exercise caution and monitor patients for adverse events when co-administering silodosin with moderate CYP3A4 inhibitors.
Strong P-glycoprotein (P-gp) Inhibitors: In vitro studies indicated that silodosin is a P-gp substrate. Concomitant use of silodosin with strong P-gp inhibitors (e.g., cyclosporine) may cause significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin is therefore not recommended in patients taking strong P-gp inhibitors.
Alpha-blockers: The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin should not be used in combination with other alpha-blockers.
The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general silodosin population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively). Exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events.
Metabolic Interactions: In vitro data indicate that silodosin does not have the potential to induce cytochrome P450 enzyme systems.
Food Interactions: The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18-43% and exposure (AUC) by 4-49% across three different studies. Safety and efficacy clinical trials for silodosin were always conducted in the presence of food intake. Patients should be instructed to take silodosin with a meal to reduce risk of adverse events.
Laboratory Test Interactions: No laboratory test interactions were observed during clinical evaluations. Treatment with silodosin for up to 52 weeks had no significant effect on prostate-specific antigen (PSA).
Adverse Reactions Observed in At least 2% of Patients:
Adverse Events Reported Between 1% and 2% of Patients:
Following Adverse Events were Reported in Single Case:
Postmarketing 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:
Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. Orthostatic hypotension was the dose-limiting adverse event. Should overdose of silodosin lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, administration of intravenous fluids and vasopressors may be considered. Renal dialysis is not expected to be beneficial because silodosin is highly (97%) protein bound.
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