Brand name: Rapaflo
Drug class: Selective alpha-1-Adrenergic Blocking Agents
ATC class: G04CA04
VA class: GU900
Chemical name: 1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-dihydro-1H-indole-7-carboxamide
Molecular formula: C₂₅H₃₂F₃N₃O₄
CAS number: 160970-54-7

Introduction

α₁-Adrenergic blocker with selectivity for α_1A-adrenergic receptors; trifluoroethoxy-phenoxyethyl amine derivative.

Uses for Silodosin

Benign Prostatic Hyperplasia (BPH)

Reduction of urinary obstruction and relief of associated manifestations (e.g., hesitancy, weak stream, sensation of incomplete bladder emptying, frequency, urgency, nocturia) in patients with symptomatic BPH.

May be a useful alternative to surgery, particularly in those who are awaiting surgical correction of hyperplasia or who are not candidates for such surgery.

May consider combined therapy with an α_1A-adrenergic blocking agent and a 5α-reductase inhibitor for men with bothersome moderate to severe BPH. Has been more effective than therapy with either drug alone in preventing long-term BPH symptom progression. Men at risk for BPH progression are most likely to benefit from combination therapy.

Other Uses

Manufacturer states that silodosin should not be used for the treatment of hypertension.

Silodosin Dosage and Administration

Administration

Oral Administration

Administer orally once daily with a meal.

Dosage

Adults

BPH

Oral

8 mg once daily.

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment (Cl_cr 50–80 mL/minute). Reduce dosage to 4 mg once daily in patients with moderate renal impairment (Cl_cr 30–50 mL/minute). Not recommended for use in patients with severe renal impairment (Cl_cr <30 mL/minute).

Cautions for Silodosin

Contraindications

• Severe hepatic impairment (Child-Pugh class C).

• Severe renal impairment (Cl_cr <30 mL/minute).

• Concomitant use with potent inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir). (See Interactions.)

Warnings/Precautions

Warnings

Orthostatic Hypotension

Potential for orthostatic hypotension, dizziness, or syncope. (See Advice to Patients.)

General Precautions

Prostate Cancer

Exclude possibility of prostate cancer prior to initiation of therapy.

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) observed during phacoemulsification cataract surgery in some patients currently receiving or previously treated with α₁-adrenergic blocking agents.

Specifically question male patients being considered for cataract surgery to determine whether they have received silodosin or other α₁-adrenergic blockers. If patient has received α₁-adrenergic blockers, ophthalmologist should consider modification of the surgical technique through use of iris hooks or iris dilator rings or pharmacologic intervention with intracameral phenylephrine or preoperative administration of atropine to minimize complications of IFIS. Benefit of discontinuing α₁-blocker therapy prior to cataract surgery not established.

Specific Populations

Pregnancy

Category B. Not indicated for use in women.

Lactation

Not indicated for use in women.

Pediatric Use

Not indicated for use in children.

Geriatric Use

Higher incidence of orthostatic hypotension reported in patients ≥65 years of age compared with younger adults. No other substantial differences in safety and efficacy relative to younger adults.

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment. (See Contraindications under Cautions.)

Renal Impairment

Use not recommended in patients with severe renal impairment. Use caution and reduce dosage in patients with moderate renal impairment.

Common Adverse Effects

Retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, nasal congestion.

Drug Interactions

Extensively metabolized by CYP3A4 and UGT2B7.

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction (increased plasma silodosin concentrations) with potent inhibitors of CYP3A4. Concomitant use contraindicated.

Drugs Affecting or Affected by P-glycoprotein Transport

Silodosin is a substrate for the P-glycoprotein transport system. Potential pharmacokinetic interaction (increased plasma silodosin concentrations) with inhibitors of P-glycoprotein transport. Concomitant use with a potent P-glycoprotein inhibitor not recommended.

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT) 2B7

Potential pharmacokinetic interaction (increased silodosin exposure) with inhibitors of UGT2B7.

Specific Drugs

Silodosin Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of approximately 32% following oral administration under fed conditions. Peak plasma concentrations attained in about 2.6 hours.

Food

When administered with a moderate-fat, moderate-calorie meal, AUC and peak plasma concentrations are decreased by 4–49% and 18–43%, respectively, compared with administration in the fasting state. Administration with a high-fat, high-calorie meal not evaluated.

Distribution

Plasma Protein Binding

Approximately 97%.

Elimination

Metabolism

Extensively metabolized in the liver via glucuronidation, alcohol and aldehyde dehydrogenases, and CYP3A4 isoenzymes. The primary active metabolite, KMD-3213G, is formed via UGT2B7-mediated glucuronidation. Another major metabolite, KMD-3293, is formed via alcohol and aldehyde dehydrogenases. KMD-3293 is not expected to contribute substantially to the overall pharmacologic activity of silodosin.

Elimination Route

Excreted in urine (33.5%) and feces (54.9%).

Half-life

Approximately 13.3 hours.

Special Populations

In patients with moderate hepatic impairment, the pharmacokinetics of silodosin were not substantially altered following administration of a single dose. The pharmacokinetics of silodosin in patients with severe hepatic impairment have not been evaluated.

In patients with moderate renal impairment, AUC, peak plasma concentrations, and elimination half-life were 3.2, 3.1, and 2 times higher, respectively, than in healthy individuals.

In geriatric individuals, AUC and elimination half-life were increased by approximately 15% and 20%, respectively, compared with younger individuals.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Actions

• Blocks α₁-adrenergic receptors in the lower urinary tract to cause relaxation of smooth muscle in the bladder neck and prostate, resulting in improved urinary flow and reduced symptoms of BPH.

• Higher affinity for α_1A-adrenergic receptors, which are in nonvascular smooth muscle (e.g., prostate), than for α_1B-adrenergic receptors located in vascular smooth muscle; may result in reduced incidence of cardiovascular effects (e.g., syncope, dizziness, hypotension).

Advice to Patients

• Risk of orthostatic hypotension (e.g., feeling faint or dizzy), particularly following initiation of therapy; importance of exercising caution when driving, operating machinery, or performing hazardous tasks.

• Importance of taking silodosin once daily with a meal.

• Risk of retrograde ejaculation. Importance of advising patients that this adverse effect occurs frequently and is reversible upon discontinuance of therapy.

• Importance of advising male patients being considered for cataract surgery that they should inform their ophthalmologist of current or prior α₁-blocker (e.g., silodosin) therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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