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 capsule 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.

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 capsule is 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 to 43% and exposure (AUC) by 4 to 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

Pregnancy Category B. Silodosin capsule is not indicated for use in women.

An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13 to 25 times the maximum recommended human exposure or MRHE of silodosin via AUC). No statistically significant teratogenicity was observed at this dose.

Silodosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated silodosin, which is present in human serum at approximately 4 times the level of circulating silodosin and which has similar pharmacological activity to silodosin.

No effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day.

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 capsules patients <65 years of age (1.2% for placebo), 2.9% of silodosin capsules patients ≥65 years of age (1.9% for placebo), and 5% of patients ≥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 capsule has 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 capsule has 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 capsule 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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