Rapaflo: Indications, Dosage, Precautions, Adverse Effects
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Rapaflo - Product Information

Manufacture: Actavis
Country: Canada
Condition: Benign Prostatic Hyperplasia
Class: Antiadrenergic agents, peripherally acting
Form: Capsules
Ingredients: Silodosin, D-mannitol, Magnesium Stearate, Pregelatinized Starch, And Sodium Lauryl Sulfate. The Size #1 And #3 Hard Gelatin Capsules Contain Gelatin And Titanium Dioxide. The #1 Capsules Are Printed With Edible Ink Containing Fdandc Blue No. 1 Aluminum Lake And Yellow Iron Oxide. The #3 Capsules Are Printed With Edible Ink Containing Yellow Iron Oxide.

Summary of product information

Route of Administration Dosage Form /Strength Clinically Relevant Nonmedicinal Ingredients
Oral Capsule, Immediate- Release, 8 mg and 4 mg For a complete listing see Dosage Forms,Composition and Packaging section.

Indications and clinical use

RAPAFLO (silodosin) is indicated for:

  • the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Geriatrics (≥ 65 years of age)

RAPAFLO has been found to be safe and effective when administered at therapeutic doses (8 mg once daily) to patients over the age of 65 years (see CLINICAL TRIALS section).

Pediatrics (< 18 years of age)

The safety and effectiveness of RAPAFLO in pediatric patients have not been established. RAPAFLO is not indicated for use in children (see WARNINGS AND PRECAUTIONS section).

Women

The safety and effectiveness of RAPAFLO in female patients have not been established. RAPAFLO is not indicated for use in women (see WARNINGS AND PRECAUTIONS section).

Contraindications

  • RAPAFLO (silodosin) is contraindicated in patients known to have hypersensitivity to silodosin or any component of the RAPAFLO formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
  • RAPAFLO should not be administered to patients with severe hepatic impairment (Child-Pugh scores ≥ 10) (see WARNINGS AND PRECAUTIONS section).
  • RAPAFLO should not be administered to patients with severe renal impairment (CCr < 30 mL/min) (see WARNINGS AND PRECAUTIONS section).
  • RAPAFLO should not be administered to patients using concomitant potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) (see WARNINGS AND PRECAUTIONS section).
  • RAPAFLO should not be administered to patients using concomitant alpha-blockers (e.g., prazosin, terazosin, doxazosin) (see WARNINGS AND PRECAUTIONS section).

Warnings and precautions

As with all α1-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with RAPAFLO, as a result of which, rarely, syncope can occur. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared (see WARNINGS AND PRECAUTIONS, Cardiovascular section and ADVERSE REACTIONS section).

Patients beginning treatment with RAPAFLO should be cautioned to avoid situations where injury could result should syncope occur.

General

Prostatic carcinoma: 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 RAPAFLO to rule out the presence of carcinoma of the prostate.

Carcinogenesis and Mutagenesis

Carcinogenicity and mutagenicity studies have been performed in animals (see TOXICOLOGY section).

Cardiovascular

RAPAFLO is not indicated for the treatment of hypertension.

Orthostatic hypotension, with or without symptoms (e.g., dizziness) may develop when beginning RAPAFLO 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.

RAPAFLO should not be administered to patients using concomitant alpha-blockers. RAPAFLO should be administered with caution to patients using other concomitant pharmaceuticals known or suspected of inducing orthostatic hypotension or syncope (see ADVERSE REACTIONS, Vascular Disorders section and DRUG INTERACTIONS, Drug-Drug Interactions section).

Endocrine and Metabolism

RAPAFLO should not be administered to patients using concomitant potent CYP3A4 inhibitors.

Hepatic

RAPAFLO should not be administered to patients with severe hepatic insufficiency (Child-Pugh scores ≥ 10).

Ophthalmologic

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 RAPAFLO.

Renal

RAPAFLO should not be administered to patients with severe renal insufficiency (CCr < 30 mL/min). In patients with moderate renal impairment (CCr 30-50 mL/min), the dose should be reduced to 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80 mL/min).

Special Populations

Pregnant Women

RAPAFLO is not indicated nor recommended for use in women. No embryotoxic and/or teratogenic effects in rats or rabbits were observed with RAPAFLO.

Nursing Women

RAPAFLO is not indicated nor recommended for use in women. It is unknown if the drug is excreted in human milk.

Pediatrics (< 18 years of age)

RAPAFLO is not indicated for use in children.

Geriatrics (≥ 65 years of age)

In double-blind, placebo-controlled, 12-week clinical studies of RAPAFLO, 259 (55.6%) patients 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 RAPAFLO patients < 65 years of age (1.2% for placebo), 2.9% of RAPAFLO 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.

Adverse reactions

Adverse Drug Reaction Overview

Retrograde ejaculation and dizziness are the most frequent adverse events with RAPAFLO. Retrograde ejaculation is reversible upon discontinuation of the drug.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In U.S. Phase 3 clinical trials, 897 patients with BPH were exposed to 8 mg RAPAFLO daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 to 87 years of age, and predominantly Caucasian. Of these patients, 42.8% were 65 years of age or older and 10.7% were 75 years of age or older.

Safety information was derived from two U.S. Phase 3 double-blind, placebo-controlled clinical studies (Studies 1 and 2) in which 466 patients were administered RAPAFLO and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of RAPAFLO treated patients (36.8% for placebo treated). A total of 6.4% of RAPAFLO treated patients (2.2% for placebo treated) discontinued therapy due to an adverse reaction (treatment-emergent), the most common reaction being retrograde ejaculation (2.8%) for RAPAFLO treated patients. Retrograde ejaculation is reversible upon discontinuation of treatment.

The incidence of adverse treatment-emergent events listed in the following table were derived from two 12-week, multicenter, double-blind, placebo-controlled clinical studies of RAPAFLO 8 mg daily in BPH patients. Adverse events that occurred in at least 2% of patients treated with RAPAFLO and more frequently than with placebo are shown in Table 1.

Table 1 Adverse Treatment-Emergent Events Occurring in ≥ 2% of Patients in 12-week, Placebo-Controlled Clinical Trials
Adverse Events RAPAFLO
(N = 466)
n (%)
Placebo
(N = 457)
n (%)
Retrograde Ejaculation 131 (28.1) 4 (0.9)
Dizziness 15 (3.2) 5 (1.1)
Diarrhea 12 (2.6) 6 (1.3)
Orthostatic Hypotension 12 (2.6) 7 (1.5)
Headache 11 (2.4) 4 (0.9)
Nasopharyngitis 11 (2.4) 10 (2.2)
Nasal Congestion 10 (2.1) 1 (0.2)

In Studies 1 and 2, treatment-related adverse events that were reported as ≥ 1% and < 2% of patients receiving RAPAFLO and occurred more frequently than with placebo are presented in Table 2.

Table 2 Treatment-Related Adverse Events Occurring in ≥ 1% and < 2% of Patients in 12-week, Placebo-Controlled Clinical Trials
Adverse Events RAPAFLO
(N = 466)
% of patients
Placebo
(N = 457)
% of patients
Nervous System Disorders
Headache

6 (1.3)

1 (0.2)
Vascular Disorders
Orthostatic Hypotension

9 (1.9)

7 (1.5)
Gastrointestinal Disorders
Diarrhea

5 (1.1)

1 (0.2)
Respiratory Thoracic and
Mediastinal Disorders

Nasal Congestion


7 (1.5)


1 (0.2)

Vascular Disorders

In two U.S. Phase 3 double-blind, placebo-controlled clinical studies (Studies 1 and 2), treatment-related dizziness was seen in 2.4% of patients receiving silodosin and 0.7% of those receiving placebo.

A test for orthostatic hypotension was conducted 2 to 6 hours after the first dose in the two 12-week, double-blind, placebo-controlled clinical studies. After the patient had been at rest in a supine position for 5 minutes, the patient was asked to stand. Blood pressure and heart rate were assessed at 1 minute and 3 minutes after standing. A positive result was defined as a > 30 mmHg decrease in systolic blood pressure, or a > 20 mmHg decrease in diastolic blood pressure, or a > 20 bpm increase in heart rate, as presented in Table 3.

Table 3 Summary of Orthostatic Test Results in 12-week, Placebo-Controlled Clinical Trials
Time of
Measurement
Test Result RAPAFLO
(N = 466)
% of patients
Placebo
(N = 457)
% of patients
1 Minute After
Standing
Negative 459 (98.7%) 454 (99.6%)
Positive 6 (1.3%) 2 (0.4%)
3 Minutes After
Standing
Negative 456 (98.1%) 454 (99.6%)
Positive 9 (1.9%) 2 (0.4%)

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Vascular Disorders

One case of syncope in a patient taking prazosin concomitantly was reported in the RAPAFLO treatment group. In a 9-month open-label safety study, loss of consciousness was observed in one patient. Because the investigator who examined this patient could not rule out the possibility that silodosin was causative, this event was considered related to silodosin use.

Post-Market Adverse Drug Reactions

The following adverse events have been identified during post-approval use of silodosin. Because these events 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:

Eye Disorders:

Cases of Intraoperative Floppy Iris Syndrome have been reported (see WARNINGS AND PRECAUTIONS, Ophthalmologic).

Hepatobiliary Disorders:

Cases of jaundice, impaired hepatic function associated with increased transaminase values, and abnormal liver function tests have been reported.

Immune System Disorders:

Cases of allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in hospitalization have been reported.

Skin and Subcutaneous Tissue Disorders:

Cases of toxic skin eruption (drug eruption), purpura, skin rash, pruritus, urticaria, angioedema, dermatitis exfoliative, swelling face, erythema and erythema multiforme have been reported.

Cardiac Disorders:

Cases of tachycardia and palpitations have been reported.

Respiratory Disorders:

Cases of dyspnoea, interstitial lung disease, eosinophilic pneumonia, and eosinophilic pneumonia (acute) have been reported.

Drug interactions

Overview

RAPAFLO is not an inducer or an inhibitor of any of the principal hepatic enzymes involved in the metabolism of other drugs.

CYP3A4 is a principal hepatic enzyme isoform involved in the metabolism of RAPAFLO.

Potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin and ritonavir, increase RAPAFLO blood levels and exposure (Area Under the Curve - AUC). RAPAFLO should not be co-administered with potent inhibitors of CYP3A4 (see CONTRAINDICATIONS). See Drug-Drug Interactions for details of increased RAPAFLO blood levels. As this is only a partial list, the physician is advised to consult current scientific literature regarding other CYP3A4 competitive inhibitors prior to prescribing RAPAFLO if other concomitant medications are used.

Moderate CYP3A4 inhibitor diltiazem increased the RAPAFLO AUC by approximately 30%, but the maximum concentration (Cmax) and half-life were not affected. No dose adjustment is required.

It is not known how combined exposure of any medications metabolized by the CYP3A4 hepatic enzyme isoform (such as alpha1-blockers), herbal remedies (particularly St. John’s Wort, Milk Thistle), and grapefruit juice may influence the overall efficacy and unwanted side effects of these medications. Therefore, caution should be exercised.

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. RAPAFLO is therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4 Established or Potential Drug-Drug Interactions
Drug / Class Reference Effect Clinical Comment
Ketoconazole, 400 mg CT Increased silodosin plasma concentration 3.7-fold Recommend not using silodosin with potent CYP3A4 inhibitors.
Potent CYP3A4 Inhibitors (ritonavir) T Increased silodosin plasma concentration Recommend not using silodosin with potent CYP3A4 inhibitors.
Strong P-glycoprotein (P-gp) Inhibitors (cyclosporine) T Increased silodosin plasma concentration Recommend not using silodosin with potent P-gp inhibitors.
Diltiazem, 300 mg CT Increased silodosin plasma AUC by 30% AUC was elevated by approximately 30%, but other parameters were not increased. No dosage adjustment needed.
Digoxin, 0.25 mg CT None Seven day co-administration did not influence the steady state pharmacokinetics of either drug.
Sildenafil, 100 mg CT In subjects < 65 years of age a mean increase in heart rate was observed during orthostatic tests, while those ≥ 65 demonstrated a slight mean decrease in blood pressure. No events of symptomatic orthostasis occurred in subjects receiving silodosin with sildenafil, nor were there any events of dizziness.
Tadalafil, 20 mg CT In subjects < 65 years of age a mean increase in heart rate was observed during orthostatic tests, while those ≥ 65 demonstrated a slight mean decrease in blood pressure. No events of symptomatic orthostasis occurred in subjects receiving silodosin with tadalafil, nor were there any events of dizziness.
Antihypertensives CT Slightly higher incidence of adverse effects when used concomitantly Approximately one-third of the patients in the two Phase 3 clinical studies used concomitant antihypertensive medications. 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.
Alpha-1 blockers T Increase in orthostatic effects The pharmacodynamic interactions may be expected, nd silodosin should not be used in com ination with other alpha- blockers.Nevertheless, exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events.

Legend: CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

The oral bioavailability of silodosin is not changed when taken with food. Food decreases Cmax by approximately 30% and increases tmax by approximately 1 hour.

RAPAFLO should be taken orally once daily with a meal.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

No laboratory test interactions were observed during clinical evaluations. Treatment with RAPAFLO for up to 52 weeks had no significant effect on prostate-specific antigen (PSA).

Dosage and administration

Dosing Considerations

Before prescribing RAPAFLO, consider the following situations that may affect dosing of the drug:

  • Potent CYP3A4 inhibitors (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism section)
  • Hepatic insufficiency (see WARNINGS AND PRECAUTIONS, Hepatic section)
  • Renal insufficiency (see WARNINGS AND PRECAUTIONS, Renal section)

Recommended Dose and Dosage Adjustment

RAPAFLO (silodosin) 8 mg once daily with a meal is recommended as the dose for the treatment of the signs and symptoms of BPH.

Renal impairment

RAPAFLO is contraindicated in patients with severe renal impairment (CCr < 30 mL/min). In patients with moderate renal impairment (CCr 30-50 mL/min), the dose should be reduced to 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80 mL/min).

Hepatic impairment

RAPAFLO has not been studied in patients with severe hepatic impairment (Child-Pugh score ≥ 10) and is therefore contraindicated in these patients. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

Missed Dose

If a dose of RAPAFLO is missed, the missed dose can be taken later the same day. If a day is missed, the missed dose should be skipped and the regular dosing schedule should be resumed.

Doses must not be doubled.

Administration

RAPAFLO should be taken orally once daily with a meal.

RAPAFLO capsules may also be administered by carefully opening the capsule and sprinkling the powder inside on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the powder. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any powder/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a RAPAFLO capsule is not recommended.

Overdosage

RAPAFLO was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose- limiting adverse event was orthostatic hypotension.

Should overdose of RAPAFLO 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

Silodosin, indicated for the treatment of benign prostatic hyperplasia (BPH), is a uroselective antagonist of post-synaptic α1A-adrenoceptors located in the prostate, prostatic capsule, bladder base, bladder neck, and prostatic urethra.

Pharmacodynamics

The clinical manifestations of benign prostatic hyperplasia (BPH) are due to bladder outlet obstruction caused by anatomical (static) and functional (dynamic) factors. The static component is related to an increase in prostate size which may not cause symptoms. The dynamic component is related primarily to an increase in smooth muscle tone in the prostate, prostatic capsule, bladder base, bladder neck, and prostatic urethra. This increased tone is mediated by the activation of α1-adrenoceptors and leads to an increased resistance to urinary voiding and the symptoms of BPH such as a hesitant, interrupted, weak stream; urgency and leaking or dribbling; and/or more frequent urination, especially at night.

The treatment effects of silodosin are related to its effects on sympathetic nervous system adrenoreceptors. These adrenoreceptors are G protein coupled transmembrane receptors that mediate catecholaminergic actions. To date, three distinct members of this family have been identified: α1A, α1B, and α1D. α1A-adrenoreceptors are expressed abundantly in the prostatic stroma, while α1D-adrenoreceptors are the predominate subtype in the nasal passages, spinal cord, and human bladder. α1A-adrenoreceptors and α1B-adrenoreceptors are both expressed within human vascular smooth muscle. However, as patients age, the ratio between these subtypes changes with α1B-adrenoreceptors becoming predominate in the vasculature, particularly in patients over 65 years of age.

Silodosin is highly selective for α1A-adrenoreceptors. Blockade of these α1A-adrenoreceptors causes smooth muscle in the prostate to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms. Silodosin has a substantially lower affinity for the α1B-adrenoreceptors.

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 and that the α1A1B binding ratio of silodosin is extremely high (162:1), while the α1A1D binding ratio of silodosin is moderate (55:1). This is illustrated in the table below.

Table 5 Affinity for Human α1A-AR subtype and α1A-AR Subtype Selectivity of Silodosin
Test Drug pKi Value α1A-AR Subtype Selectivitya)
α1A-AR α1B-AR α1D-AR α1A1B Ratio α1A1D Ratio
silodosin (KMD-3213) 10.4 ±0.07 8.19±0.04 8.66±0.02 162 55.0

The pKi value in the table represents the mean ± S.E. of 3 runs.
a) The subtype selectivity (α1A1B and α1A1D ratios) was calculated from the ratio after converting the concentration, specifically, using 10M [M=pKi (α1A) – pKi (α1B or α1D)]. (Example: M=10.4-8.18 = 2.21 102.21 = 162)

In placebo-controlled clinical studies in patients with BPH, RAPAFLO was shown to significantly increase average urine peak flow rate (Qmax) by 30% which is observed after the first dose. These favorable urodynamic effects may have been responsible for the improvement of lower tract irritative and obstructive symptoms that were observed. The Quality of Life Index also significantly improved in the RAPAFLO patients.

Electrocardiography

The effect of RAPAFLO on QT interval was evaluated in a double-blind, randomized, active- (moxifloxacin) and placebo-controlled, parallel-group study in 183 healthy male subjects aged 18 to 45 years. Subjects received RAPAFLO 8 mg, RAPAFLO 24 mg, or placebo once daily for 5 days, or a single dose of moxifloxacin 400 mg on Day 5 only. The 24 mg dose of RAPAFLO was selected to achieve blood levels of silodosin that may be seen in a “worst-case” scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors). QT interval was measured during a 24-hour period following dosing on Day 5 (at silodosin steady state).

In 183 patients analyzed, RAPAFLO was not associated with an increase in individual corrected (QTcI) QT interval at any time during steady state measurement, while moxifloxacin, the active control, was associated with a maximum 9.59 msec increase in QTcI.

There has been no signal of Torsade de Pointes in the post-marketing experience of silodosin.

Pharmacokinetics

The pharmacokinetics of silodosin have been evaluated in adult male subjects with doses ranging from 0.1 mg to 24 mg per day. The pharmacokinetics of silodosin are linear throughout this dosage range.

Absorption:

The pharmacokinetic characteristics of silodosin 8 mg once daily were determined in a multi- dose, open-label, 7-day pharmacokinetic study completed in 19 healthy, target-aged (≥ 45 years of age) male subjects. Table 6 and Figure 1 present the steady state pharmacokinetics of this study.

Table 6 Mean (±SD) Steady State Pharmacokinetic Parameters in Males Following Silodosin 8 mg Once Daily with a Meal
Cmax
(ng/mL)
tmax
(hours)
t1/2
(hours)
AUCss
(ng•hr/mL)
61.6 ± 27.54 2.6 ± 0.90 13.3 ± 8.07 373.4 ± 164.94

Cmax = maximum concentration, tmax = time to reach Cmax, t1/2 = elimination half-life,
AUCss = steady state area under the concentration-time curve

Figure 1 Mean (±SD) Silodosin Steady State Plasma Concentration-Time Profile in Healthy Target-Aged Subjects following Silodosin 8 mg Once Daily with Food


The absolute bioavailability is approximately 32%.

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.

Distribution:

Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound.

Metabolism:

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) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Co-administration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, fluconazole) may potentially increase exposure to silodosin. KMD-3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately 4 times greater than that of silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin. KMD-3293 is not expected to contribute significantly to the overall pharmacologic activity of RAPAFLO.

Excretion:

Following oral administration of 14C-labeled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in urine and 54.9% in feces. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour.

Special Populations and Conditions

Pediatric:

RAPAFLO has not been evaluated in patients less than 18 years of age.

Geriatric:

A study comparing 16 males 65 to 75 years of age, 15 males > 75 years of age, and 16 males 45 to 64 years of age was conducted. The exposure (AUC) and elimination half-life of silodosin were approximately 10% less and 17% greater, respectively, in geriatric males 65 to 75 years of age than the younger subjects, and approximately 16% less and 35% greater, respectively in geriatric males > 75 years of age than the younger subjects. A decrease in Cmax of 13% and 40% was seen in males 65 to 75 years of age and > 75 years of age, respectively. Because of the modest degree of these changes, no dose adjustment is needed in elderly subjects (see WARNINGS AND PRECAUTIONS, Geriatrics section).

Gender:

RAPAFLO has not been evaluated in women.

Race:

No clinical studies specifically investigating the effects of race have been performed. However, available clinical data do not suggest clinically important differences.

Hepatic Insufficiency:

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 pharmacokinetic disposition of silodosin was not significantly altered in the patients with moderate hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. The pharmacokinetics of silodosin in patients with severe hepatic impairment have not been studied. RAPAFLO should not be administered to patients with severe hepatic impairment (Child-Pugh scores ≥ 10).

Renal Insufficiency:

In a study with six subjects with moderate renal impairment, the total silodosin (bound and unbound) AUC, Cmax, and elimination half-life were 3.2-, 3.1-, and 2-fold higher, respectively, compared to seven subjects with normal renal function. The unbound silodosin AUC and Cmax were 2.0- and 1.5-fold higher, respectively, in subjects with moderate renal impairment compared to the normal controls.

In another study with eight subjects with mild and moderate renal impairment, and five subjects with severe renal impairment, the total silodosin AUC, Cmax, and elimination half-life were 1.9-, 1.7-, and 1.3-fold higher for the mild, and 2.2-, 1.5-, and 1.7-fold higher for moderate compared to eight subjects with normal renal function. The increase in exposure to unbound silodosin was greater in patients with severe renal impairment (Cmax and AUC 2.2- and 3.7-fold, respectively, compared to subjects with normal renal function) than in patients with moderate and mild impairment (Cmax and AUC 1.6- and 1.8-fold, respectively).

In controlled and uncontrolled clinical studies, the incidence of orthostatic hypotension and dizziness was greater in subjects with moderate renal impairment treated with 8 mg RAPAFLO daily than in subjects with normal or mildly impaired renal function.

RAPAFLO is contraindicated in patients with severe renal impairment (CCr < 30 mL/min). In patients with moderate renal impairment (CCr 30-50 mL/min), the dose should be reduced to 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80 mL/min).

Storage and stability

Store at controlled room temperature (15oC to 30oC). Keep out of reach of children. Protect from light and moisture.

Special handling instructions

There are no special handling instructions.

Dosage forms, composition and packaging

Each RAPAFLO 8 mg capsule for oral administration contains 8 mg silodosin, and the following inactive ingredients: D-mannitol, magnesium stearate, pregelatinized starch, and sodium lauryl sulfate. The size #1 hard gelatin capsules contain gelatin and titanium dioxide. The capsules are printed with edible ink containing FD&C Blue No. 1 Aluminum Lake and yellow iron oxide. Cap is imprinted with “WATSON 152” in green. Body is imprinted with “8 mg” in green. 8 mg capsules are supplied in unit of use HDPE bottles of:

  • 30 capsules
  • 90 capsules

Not all pack sizes may be available on the Canadian market.

Each RAPAFLO 4 mg capsule for oral administration contains 4 mg silodosin, and the following inactive ingredients: D-mannitol, magnesium stearate, pregelatinized starch, and sodium lauryl sulfate. The size #3 hard gelatin capsules contain gelatin and titanium dioxide. The capsules are printed with edible ink containing yellow iron oxide. Cap is imprinted with “WATSON 151” in gold. Body is imprinted with “4 mg” in gold. 4 mg capsules are supplied in unit of use HDPE bottles of:

  • 30 capsules
  • 90 capsules

Not all pack sizes may be available on the Canadian market.