Silodosin - Dosage, Uses, Adverse Effects, and Precautions

Overview

Silodosin is a medication in the alpha-blocker class. It is primarily used to treat lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). It is considered a novel and more selective alpha-blocker, specifically targeting the lower urinary tract, which may result in fewer side effects than other alpha-blockers.

Silodosin acts as a selective antagonist of alpha(α)-1 adrenergic receptors, particularly the α1A subtype, which is predominant in regulating smooth muscle tone in the bladder, neck, prostate, and prostatic urethra.

By binding to α1A-adrenoceptors with high affinity, Silodosin effectively relaxes the lower urinary tract, thereby improving urinary symptoms and alleviating bladder outlet obstruction associated with BPH. Silodosin is available in oral capsules, and it was approved by the FDA (Food and Drug Administration) in October 2008 for the symptomatic treatment of BPH in adults.

Clinical Efficacy and Safety of Silodosin

Silodosin has been found to effectively improve lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) with minimal side effects. Clinical studies have shown significant improvements in symptom scores and urinary flow rates compared to placebo. The most common adverse effect is retrograde or abnormal ejaculation, while orthostatic hypotension occurs infrequently. Overall, silodosin is considered clinically useful and well-tolerated for treating BPH-related LUTS.

For Patients:

What Is Silodosin?

Silodosin is a medication used in men to address symptoms associated with an enlarged prostate, medically termed benign prostatic hyperplasia (BPH). These symptoms include challenges with urination, such as hesitation, dribbling, a weak stream, incomplete bladder emptying, and painful urination, as well as urinary frequency and urgency. Silodosin falls under the category of medications known as alpha-blockers. Its mechanism of action involves relaxing the bladder and prostate muscles and alleviating BPH symptoms.

What Is Benign Prostatic Hyperplasia?

Benign prostatic hyperplasia (BPH) is a common health condition that typically occurs with advancing age. Also known as an enlarged prostate, BPH involves the enlargement of the prostate gland, which is situated just below the bladder and surrounds part of the urethra. As the prostate grows larger, it can lead to symptoms that may disrupt urine flow out of the bladder, potentially causing issues with bladder, urinary tract, or kidney function.

While BPH is not cancerous, its symptoms can sometimes indicate more serious conditions, including prostate cancer. Treatment options for BPH vary and may include medications, surgical interventions, or other procedures, depending on factors such as the severity of symptoms, the size of the prostate, and the presence of other health conditions.

How Does Silodosin Work?

Silodosin is a medication used by men to manage symptoms related to an enlarged prostate, medically known as benign prostatic hyperplasia (BPH). Unlike medications that shrink the prostate, Silodosin works by relaxing the muscles within the prostate and bladder. This action helps to alleviate BPH symptoms such as difficulty initiating urine flow, a weak urine stream, and the frequent or urgent need to urinate, including at night. Silodosin is classified as an alpha-blocker and should not be employed to treat high blood pressure.

How Should the Patient Take Silodosin?

Silodosin should be taken orally as a capsule, typically with food, once daily. It is important not to take Silodosin on an empty stomach. For consistency in the drug concentration in the blood, take Silodosin at approximately the same time each day. Follow the directions on the prescription label closely.

Take Silodosin exactly as the doctor directs, without taking more or less of it or more frequently than prescribed. While Silodosin helps control the symptoms of BPH, it does not cure it. Therefore, continue taking Silodosin even if feeling well, and do not discontinue it without consulting the doctor.

What Are the Side Effects of Silodosin?

Side effects of Silodosin may include dizziness, lightheadedness, and ejaculation problems. It is important to inform the doctor or pharmacist if these effects persist or worsen. To reduce the risk of dizziness and lightheadedness, it is recommended to rise slowly slowly from a sitting or lying position. While most people using this medication do not experience serious side effects, it is crucial to report any serious side effects, such as fainting, immediately to the doctor.

Rarely, males may experience a painful or prolonged erection lasting four or more hours, which requires immediate medical attention to prevent permanent problems. Additionally, while allergic reactions to Silodosin are rare, seek medical help promptly if experiencing symptoms such as rash, swelling, severe dizziness, or difficulty breathing.

What Are the Things to Inform the Doctor Before Taking Silodosin?

Before taking Silodosin, individuals should inform their doctor or pharmacist if they are allergic to it or other medications. Additionally, they should disclose if they are taking antifungals, HIV (human immunodeficiency virus) protease inhibitors, or other medications, as they may interact with Silodosin.

It is important to inform the healthcare provider about their medical history, particularly if they have kidney or liver disease, low blood pressure, or certain eye problems. Silodosin is only for use in men; women, especially if pregnant or breastfeeding, should not take it. Individuals should also inform their doctor if they are scheduled for surgery or dental surgery and mention if they have experienced drowsiness or dizziness, especially when starting Silodosin.

Furthermore, older people may be more susceptible to its side effects, particularly dizziness and low blood pressure.

How Should the Patient Store Silodosin?

Silodosin should be stored in its original container, tightly closed, and out of reach of children. It should be kept at room temperature and away from excess heat and moisture, avoiding storage in the bathroom. Unused medication should be disposed of properly to avoid accidental ingestion by pets, children, or others. Flushing Silodosin down the toilet is not recommended. Instead, it should be disposed of through a medicine take-back program. To avoid accidental ingestion by children, all medications should be kept out of sight and reach. Safety caps should be locked, and medications should be placed in a secure location, away from the sight and reach of children.

For Doctors:

Indication and Usage: Silodosin is indicated for treating signs and symptoms associated with benign prostatic hyperplasia (BPH). This condition commonly affects men as they age and leads to an increase in the size of the prostate gland, which is located below the bladder. The enlargement can cause certain muscles in the gland to tighten, obstructing the urethra, the tube that carries urine from the bladder. This obstruction results in urinary difficulties such as frequent urination, a weak urine stream, and the sensation of incomplete bladder emptying.

Dosage and Administration: Silodosin is typically administered orally at a dosage of eight mg (milligrams) once daily with a meal for adults aged 18 to 64. The safety and efficacy of Silodosin have not been established for children under 18 years of age; hence, it is not recommended for this age group.

Dosage adjustments may be necessary for seniors aged 65 and older due to potential age-related decline in liver or kidney function. As these organs may not process the medication as efficiently, there is a risk of increased side effects if the drug accumulates in the body. Therefore, healthcare providers might modify the dosage or choose not to prescribe Silodosin based on the individual's hepatic and renal health.

Clinical Pharmacology

1. Mechanism of Action: Silodosin operates as a selective antagonist of α1-adrenoceptors, strongly favoring the α1A-adrenoceptor subtype. In the bladder, neck, and prostate, these receptors are crucial for regulating smooth muscle tone. Under normal conditions, the binding of norepinephrine and epinephrine to α1-adrenoceptors activates a signaling cascade that increases intracellular calcium levels, leading to smooth muscle contraction.

By blocking α1A-adrenoceptors, Silodosin disrupts this signaling pathway, relaxing prostatic and urethral smooth muscles. This relaxation alleviates lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), such as hesitancy, slow stream, and incomplete emptying. Additionally, Silodosin’s action on α1D-adrenoceptors helps to reduce bladder storage symptoms like frequency, urgency, and nocturia by targeting afferent nerves and alleviating bladder overactivity.

2. Pharmacokinetics:

• Absorption: Silodosin has an absolute bioavailability of approximately 32 percent. Following oral administration of an eight mg dose in healthy male subjects, the peak plasma concentration (Cmax) is 61.6 ng/mL (nanograms per milliliter) with an area under the curve (AUC) of 373.4 ng x hr/mL (hours per milliliter). The time to reach peak concentration (Tmax) is about 2.6 hours. The main metabolite, Silodosin glucuronide (KMD-3213G), shows an AUC three to four times higher than the parent compound. Taking Silodosin with a moderate-fat or moderate-calorie meal reduces the Cmax by 18 to 43 percent, AUC by four to 49 percent, and delays Tmax by about one hour.

• Volume of Distribution: Silodosin's apparent volume of distribution is 49.5 liters.

• Protein Binding: Silodosin is approximately 97 percent bound to plasma proteins.

• Route of Elimination: Following oral administration, approximately 33.5 percent of the Silodosin dose is excreted in urine, and 54.9 percent is recovered in feces over 10 days.

• Half-Life: The elimination half-life of Silodosin is approximately 13.3 hours. The main metabolite, Silodosin glucuronide, has a longer half-life of about 24 hours.

• Clearance: The plasma clearance rate of Silodosin after intravenous administration is about 10 liters per hour.

3. Pharmacodynamics: Silodosin is an antagonist of α1-adrenoceptors, with the highest selectivity for the α1A-adrenoceptor subtype. This selectivity is significantly higher, with a 162-fold greater affinity for α1A-adrenoceptors compared to α1B-adrenoceptors and about a 50-fold greater affinity than α1D-adrenoceptors. This specificity is crucial for its therapeutic effects in treating benign prostatic hyperplasia (BPH).

Clinical trials have demonstrated that Silodosin effectively improves the maximum urinary flow rate and alleviates both voiding and storage symptoms associated with BPH. The therapeutic effects are rapid, with noticeable relief of lower urinary tract symptoms occurring within two to six hours after oral administration.

In terms of cardiac effects, Silodosin inhibits the human ether-a-go-go-related gene (HERG) tail current, which is associated with cardiac ion channels. However, silodosin's cardiovascular effects are generally weak, making it a safer option compared to less selective α1-adrenoceptor antagonists.

A notable side effect of Silodosin, like other α1-adrenoceptor antagonists, is the potential to cause intraoperative floppy iris syndrome (IFIS). This condition occurs during cataract surgery and is characterized by small pupils, a flaccid, and a billowing iris, which can complicate the surgical procedure. Patients undergoing cataract surgery should inform their ophthalmologist about using Silodosin to manage this risk appropriately.

Usage In Specific Populations:

Renal Impairment

• Mild Renal Dysfunction (CrCl (Creatinine Clearance) 50 to 80 mL/min): No dosage adjustment is recommended.

• Moderate Renal Dysfunction (CrCl 30 to 50 mL/min): Taking four mg daily with food is recommended. Plasma concentrations of Silodosin are approximately three times greater in patients with moderate renal impairment compared to those with normal renal function, necessitating dosage adjustment and careful monitoring for adverse effects.

• Severe Renal Dysfunction (CrCl less than 30 mL/min): The use of Silodosin is contraindicated due to a lack of safety data and the potential for increased drug accumulation and adverse effects.

Hepatic Impairment

• Mild to Moderate Liver Dysfunction: No dosage adjustment is necessary. A study comparing patients with moderate hepatic impairment (Child-Pugh scores 7 to 9) to healthy subjects showed no noticeable alteration in the pharmacokinetics of Silodosin.

• Severe Liver Dysfunction (Child-Pugh 10 or greater): The use of Silodosin is contraindicated in this population, as it has not been studied, and the potential risks outweigh the benefits.

• Pediatric Use: Silodosin is not recommended for pediatric patients. The safety and effectiveness of Silodosin in children have not been established.

• Geriatric Use: In clinical studies, there were no noticeable differences in the safety or effectiveness of Silodosin between older (65 years and older) and younger patients. However, the incidence of orthostatic hypotension was slightly higher in older patients, particularly those aged 75 and over. Therefore, while no specific dosage adjustment is recommended solely based on age, careful monitoring for orthostatic hypotension and other adverse effects is advised in the elderly population.
• Pregnancy and Lactation: Silodosin is not indicated for use in females, including those who are pregnant or lactating. There is no relevant data on its effects in these populations, as it is intended for use in treating male-specific conditions.
• Infertility: In animal studies, Silodosin showed potential effects on male fertility at exposure levels at least twice the maximum recommended human dose (based on AUC). These findings may be reversible, but their clinical relevance in humans is unknown. Men should be aware of these potential effects if they are concerned about fertility.

Contraindications of Silodosin

• Severe Renal Impairment: Patients with a creatinine clearance (CCr) of less than 30 mL/min (milliliters per minute) should not use Silodosin due to the risk of significant drug accumulation and potential adverse effects.

• Severe Hepatic Impairment: Use is contraindicated in patients with a Child-Pugh score greater than 10. Silodosin has not been studied in this population, and the potential risks outweigh the benefits.

• Concomitant Use with Strong CYP3A4 Inhibitors: Co-administration with strong inhibitors of the cytochrome P450 3A4 (CYP3A4) enzyme, such as Ketoconazole, Clarithromycin, Itraconazole, and Ritonavir, is contraindicated. These medications can significantly increase the plasma concentration of Silodosin, leading to a heightened risk of adverse effects.

• Hypersensitivity: Patients with a known hypersensitivity to Silodosin or any of the formulation's ingredients should not take the medication. Hypersensitivity reactions may include symptoms such as rash, pruritus, or more severe allergic responses.

What Are the Adverse Effects of Silodosin?

The adverse effects of Silodosin include retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. These effects were observed in clinical trials and reported in at least two percent of patients treated with Silodosin. Additionally, postmarketing experience has identified skin and subcutaneous tissue disorders, hepatobiliary disorders, and immune system disorders as potential adverse reactions to Silodosin.

Warnings and Precautions of Silodosin

• Orthostatic Effects: Silodosin may cause postural hypotension, with or without symptoms such as dizziness, especially at the initiation of treatment. It is recommended that patients refrain from performing hazardous activities such as driving or operating machinery until they know how Silodosin affects them.

• Renal Impairment: Plasma concentrations of Silodosin are significantly increased in patients with moderate renal impairment. Dosage adjustment is necessary for these patients to mitigate the risk of adverse events. Silodosin is contraindicated in cases of severe renal impairment.

• Hepatic Impairment: Silodosin should not be prescribed to patients with severe hepatic impairment because it has not been studied in this population.

• Pharmacokinetic and Pharmacodynamic Drug Interactions: Silodosin has the potential for significant drug interactions, particularly with strong CYP3A4 inhibitors and other alpha-blockers. Co-administration with these medications should be avoided.

• Carcinoma of the Prostate: Before initiating Silodosin therapy, patients should undergo an evaluation to rule out the presence of carcinoma of the prostate, as symptoms of prostate cancer and benign prostatic hyperplasia (BPH) can overlap.

• Intraoperative Floppy Iris Syndrome: Patients planning cataract surgery should inform their ophthalmologist if they take Silodosin, as it may increase the risk of intraoperative floppy iris syndrome.

• Laboratory Test Interactions: Silodosin does not interfere with laboratory tests, including prostate-specific antigen (PSA) levels.

• Allergic Reactions: Patients with hypersensitivity to Silodosin or its components should not use the medication.

Drug Interactions of Silodosin

• Moderate and Strong CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors like Ketoconazole is contraindicated due to significant increases in Silodosin plasma concentrations. Moderate CYP3A4 inhibitors may also increase Silodosin levels, necessitating caution and monitoring.

• Strong P-glycoprotein (P-gp) Inhibitors: Silodosin is a P-gp substrate, and concurrent use with strong P-gp inhibitors like Cyclosporine is not recommended due to potential increases in Silodosin concentration.

• Alpha-Blockers: Due to potential pharmacodynamic interactions, Silodosin should not be used concomitantly with other alpha-blockers.

• Digoxin: Co-administration with Digoxin does not significantly alter Digoxin’s pharmacokinetics, and no dose adjustment is required.

• PDE5 Inhibitors: Co-administration with PDE5 inhibitors may increase the risk of orthostatic effects, although no symptomatic events were reported in clinical studies.

• Antihypertensives: Caution is advised when using Silodosin with antihypertensive medications, as there may be an increased risk of dizziness and orthostatic hypotension.

• Food Interactions: Food intake can affect the pharmacokinetics of Silodosin, so it is recommended to take Silodosin with a meal to minimize the chance of adverse effects.

Clinical Studies:

Clinical studies evaluating Silodosin showed significant improvements in symptoms of benign prostatic hyperplasia (BPH) compared to placebo. These improvements were measured using the International Prostate Symptom Score (IPSS) and the maximum urinary flow rate (Qmax). Silodosin demonstrated statistically significant reductions in IPSS total score and increases in Qmax from baseline to week 12 compared to placebo in two 12-week, randomized, double-blind, placebo-controlled studies. These improvements were observed early and sustained throughout the treatment period.