Rapaflo Information
Rapaflo () Indications And Usage
Rapaflo () , a selective alpha-1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [ ]. Rapaflo () is not indicated for the treatment of hypertension.
Rapaflo () Dosage And Administration
Renal impairment: Rapaflo () is contraindicated in patients with severe renal impairment (CCr
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 [ ].
Rapaflo () Dosage Forms And Strengths
The 8 mg capsules are white, opaque, hard #1 gelatin capsules imprinted with “WATSON 152” in green on the cap and “8 mg” in green on the body.
The 4 mg capsules are white, opaque, hard #3 gelatin capsules imprinted with “WATSON 151” in gold on the cap and “4 mg” in gold on the body.
Rapaflo () Warnings And Precautions
In a clinical pharmacology study, plasma concentrations (AUC and C) of silodosin were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal function, while half-lives of silodosin doubled in duration. The dose of Rapaflo () should be reduced to 4 mg in patients with moderate renal impairment. Exercise caution and monitor such patients for adverse events [ ].
Rapaflo () is contraindicated in patients with severe renal impairment [ ].
The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and Rapaflo () should not be used in combination with other alpha-blockers [ ].
A specific pharmacodynamic interaction study between silodosin and antihypertensive agents has not been performed. However, patients in the Phase 3 clinical studies taking concomitant antihypertensive medications with Rapaflo () did not experience a significant increase in the incidence of syncope, dizziness, or orthostasis. Nevertheless, exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events [ ].
Caution is also advised when alpha-adrenergic blocking agents including Rapaflo () are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension [ ].
Rapaflo () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In U.S. 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.
In double-blind, placebo controlled, 12-week clinical trials, 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). The majority (72.1%) of adverse reactions for the Rapaflo () treated patients (59.8% for placebo treated) were qualified by the investigator as mild. 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 treatment-emergent adverse reactions 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 reactions that occurred in at least 2% of patients treated with Rapaflo () and more frequently than with placebo are shown in Table 1.
In the two 12-week, placebo-controlled clinical trials, the following adverse events were reported by between 1% and 2% of patients receiving Rapaflo () and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia, and rhinorrhea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the Rapaflo () treatment group.
In a 9-month open-label safety study of Rapaflo () , one case of Intraoperative Floppy Iris Syndrome (IFIS) was reported.
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:
Hepatobiliary disorders:
Rapaflo () Drug Interactions
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 Rapaflo () is contraindicated [ ].
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 Rapaflo () . Exercise caution and monitor patients for adverse events when co-administering Rapaflo () with moderate CYP3A4 inhibitors.
In vitro
see
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 Rapaflo () . 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 [ ].
In vitro
Rapaflo () Use In Specific Populations
Pregnancy Category B. Rapaflo () is not indicated for use in women.
An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13-25 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.
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.
Rapaflo () should be reduced to 4 mg per day in patients with moderate renal impairment. Exercise caution and monitor patients for adverse events.
Rapaflo () has not been studied in patients with severe renal impairment. Rapaflo () is contraindicated in patients with severe renal 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.
Rapaflo () has not been studied in patients with severe hepatic impairment. Rapaflo () is contraindicated in patients with severe hepatic impairment [ ].
Rapaflo () Overdosage
Rapaflo () 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 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.
Rapaflo () Description
Rapaflo () is the brand name for silodosin, a selective antagonist of alpha-1 adrenoreceptors. The chemical name of silodosin is 1-(3-Hydroxypropyl)-5-[(2)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1-indole-7-carboxamide and the molecular formula is CHFNO with a molecular weight of 495.53. The structural formula of silodosin is:
Silodosin is a white to pale yellowish white powder that melts at approximately 105 to 109°C. It is very soluble in acetic acid, freely soluble in alcohol, and very slightly soluble in water.
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.
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.
Rapaflo () Clinical Pharmacology
Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms.
An 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.
A test for postural 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 [ ].
The effect of Rapaflo () on QT interval was evaluated in a double-blind, randomized, active- (moxifloxacin) and placebo-controlled, parallel-group study in 189 healthy male subjects aged 18 to 45 years. Subjects received either Rapaflo () 8 mg, Rapaflo () 24 mg, or placebo once daily for five 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).
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 with silodosin outside the United States.
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.
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 3 presents the steady state pharmacokinetics of this study.
The absolute bioavailability is approximately 32%.
Food Effect
The maximum effect of food (i.e., co-administration with a high fat, high calorie meal) on the PK of silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin C by approximately 18 − 43% and AUC by 4 − 49% across three different studies.
Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound.
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 to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four 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 () .
Following oral administration of C-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.
Race
No clinical studies specifically investigating the effects of race have been performed.
Geriatric
In a study comparing 12 geriatric males (mean age 69 years) and 9 young males (mean age 24 years), the exposure (AUC) and elimination half-life of silodosin were approximately 15% and 20%, respectively, greater in geriatric than young subjects. No difference in the C of silodosin was observed [ ].
Pediatric
Rapaflo () has not been evaluated in patients less than 18 years of age.
Renal Impairment
In a study with six subjects with moderate renal impairment, the total silodosin (bound and unbound) AUC, C, 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 C were 2.0- and 1.5-fold higher, respectively, in subjects with moderate renal impairment compared to the normal controls.
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 [ ].
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 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 [ ].
Cytochrome P450 (CYP) 3A4 Inhibitors
Two clinical drug interaction studies were conducted in which a single oral dose of silodosin was co-administered with the strong CYP3A4 inhibitor, ketoconazole, at doses of 400 mg and 200 mg, respectively, once daily for 4 days. Co-administration of 8 mg silodosin with 400 mg ketoconazole led to 3.8-fold increase in silodosin C and 3.2-fold increase in AUC. Co-administration of 4 mg silodosin with 200 mg ketoconazole led to similar increases: 3.7- and 2.9-fold in silodosin C and AUC, respectively. Silodosin is contraindicated with strong CYP3A4 inhibitors.
The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated. Due to the potential for increased exposure to silodosin, caution should be exercised when co-administering silodosin with moderate CYP3A4 inhibitors, particularly those that also inhibit P-glycoprotein (e.g., verapamil, erythromycin).
P-glycoprotein (P-gp) Inhibitors
Digoxin
The effect of silodosin on the pharmacokinetics of digoxin was evaluated in a multiple dose, single-sequence, crossover study of 16 healthy males, aged 18 to 45 years. A loading dose of digoxin was administered as 0.5 mg twice daily for one day. Following the loading doses, digoxin (0.25 mg once daily) was administered alone for seven days and then concomitantly with silodosin 4 mg twice a day for the next seven days. No significant differences in digoxin AUC and C were observed when digoxin was administered alone or concomitantly with silodosin.
Other Metabolic Enzymes and Transporters
In vitro
Rapaflo () Clinical Studies
Rapaflo () How Supplied/storage And Handling
8 mg capsules are supplied in non-unit of use HDPE bottles of:
Bottles of 30 and 90 capsules are supplied with child-resistant closures.
Bottles of 30 and 90 capsules are supplied with child-resistant closures.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP controlled room temperature.] Protect from light and moisture.
Rapaflo () Patient Counseling Information
Patients should be instructed to take Rapaflo () once daily with a meal.
Patients should be instructed about the possible occurrence of symptoms related to postural hypotension (such as dizziness), and should be cautioned about driving, operating machinery, or performing hazardous tasks until they know how Rapaflo () will affect them. This is especially important for those with low blood pressure or who are taking antihypertensive medications.
The most common side effect seen with Rapaflo () is an orgasm with reduced or no semen. This side effect does not pose a safety concern and is reversible with discontinuation of the product.
The patient should be instructed to tell his ophthalmologist about the use of Rapaflo () before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking Rapaflo () .
Manufactured by:Watson Laboratories, Inc.Corona, CA 92880 USA
Distributed by:Watson Pharma, Inc.Morristown, NJ 07962 USA
Under license from:Kissei Pharmaceutical Co., Ltd.Nagano, Japan
Address medical inquiries to:WATSONMedical CommunicationsP.O. Box 1953Morristown, NJ 07962-1953800-272-5525
For additional information see: or call 1-866-Rapaflo () (727-2356)
Revised: November 2009
173761-2S1109
