Silodosin (Page 2 of 5)
6.2 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:
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
7 DRUG INTERACTIONS
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 are 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. Exercise caution and monitor patients for adverse events when co-administering silodosin capsules with moderate CYP3A4 inhibitors.
7.2 Strong P-glycoprotein (P-gp) Inhibitors
In vitro studies indicated that silodosin is a P-gp substrate. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin capsules are therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine [see Clinical Pharmacology ( 12.3)].
7.3 Alpha-Blockers
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 Warnings and Precautions ( 5.5)].
7.4 Digoxin
The effect of co-administration of silodosin capsules and digoxin 0.25 mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of silodosin capsules and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required.
7.5 PDE5 Inhibitors
Co-administration of silodosin capsules with a single dose of 100 mg sildenafil or 20 mg tadalafil was evaluated in a placebo-controlled clinical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital signs were monitored in the 12-hour period following concomitant dosing. During this period, the total number of positive orthostatic test results was greater in the group receiving silodosin capsules plus a PDE5 inhibitor compared with silodosin capsules alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin capsules with a PDE5 inhibitor.
7.6 Other Concomitant Drug Therapy
Antihypertensives
The pharmacodynamic interactions between silodosin and antihypertensives have not been rigorously investigated in a clinical study. However, approximately one-third of the patients in clinical studies used concomitant antihypertensive medications with silodosin capsules. 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 [see Warnings and Precautions ( 5.5)].
Metabolic Interactions
In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.
7.7 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 capsules 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 [see Clinical Pharmacology ( 12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Silodosin capsules are not indicated for use in females.
8.2 Lactation
Silodosin capsules are not indicated for use in females.
8.3 Females 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 [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
Silodosin capsules are not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
In double-blind, placebo-controlled, 12-week clinical studies of silodosin capsules, 259 (55.6%) 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 capsule patients less than 65 years of age (1.2% for placebo), 2.9% of silodosin capsule patients greater than or equal to 65 years of age (1.9% for placebo), and 5.0% of patients greater than or equal to 75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients [see Clinical Pharmacology ( 12.3)].
8.6 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 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 have not been studied in patients with severe renal impairment. Silodosin capsules are contraindicated in patients with severe renal impairment [see Contraindications ( 4), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
8.7 Hepatic 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 have not been studied in patients with severe hepatic impairment. Silodosin capsules are contraindicated in patients with severe hepatic impairment [see Contraindications (4), Warnings and Precautions ( 5.3) and Clinical Pharmacology (12.3)].
10 OVERDOSAGE
Silodosin capsules was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was postural hypotension.
Should overdose of silodosin capsules 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 maintaining the patient in the supine position. If this measure is inadequate, administration of intravenous fluid should be considered. If necessary, vasopressors could be used, and renal function should be monitored and supported as needed. Dialysis is unlikely to be of significant benefit since silodosin is highly (97%) protein bound.
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