Source: FDA, National Drug Code (US) Revision Year: 2020
Postural 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 [see ADVERSE REACTIONS (6), USE IN SPECIFIC POPULATIONS (8.5), CLINICAL PHARMACOLOGY (12.2), and PATIENT COUNSELING INFORMATION (17)].
In a clinical pharmacology study, plasma concentrations (AUC and Cmax) 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 [see USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].
RAPAFLO is contraindicated in patients with severe renal impairment [see CONTRAINDICATIONS (4)].
RAPAFLO has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients [see CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].
In a drug interaction study, co-administration of a single 8 mg dose of RAPAFLO with 400 mg ketoconazole, a strong CYP3A4 inhibitor, caused a 3.8-fold increase in maximum plasma silodosin concentrations and 3.2-fold increase in silodosin exposure (i.e., AUC). Concomitant use of ketoconazole or other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) is therefore contraindicated [see DRUG INTERACTIONS (7.1)].
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 [see DRUG INTERACTIONS (7.3)].
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 [see ADVERSE REACTIONS (6.1) and DRUG INTERACTIONS (7.6)].
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 [see DRUG INTERACTIONS (7.5)].
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.
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 [see ADVERSE REACTIONS (6.1)].
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).
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.
Table 1. Adverse Reactions Occurring in ≥2% of Patients in 12-week, Placebo-Controlled Clinical Trials:
| Adverse Reactions | 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 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: 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
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 [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 RAPAFLO. Exercise caution and monitor patients for adverse events when co-administering RAPAFLO with moderate CYP3A4 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 [see CLINICAL PHARMACOLOGY (12.3)].
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 [see WARNINGS AND PRECAUTIONS (5.5)].
The effect of co-administration of RAPAFLO 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 RAPAFLO and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required.
Co-administration of RAPAFLO 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 RAPAFLO plus a PDE5 inhibitor compared with RAPAFLO alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving RAPAFLO with a PDE5 inhibitor.
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 [see WARNINGS AND PRECAUTIONS (5.5)].
In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.
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 RAPAFLO 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)].
RAPAFLO is not indicated for use in females.
RAPAFLO is not indicated for use in females.
Possible effects on male fertility could be observed based on findings in rats at exposures that were at least two times higher than at the MRHD (based on AUC). These findings may be reversible, and the clinical relevance is unknown [see NONCLINICAL TOXICOLOGY (13.1)].
RAPAFLO is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.
In double-blind, placebo-controlled, 12-week clinical studies of RAPAFLO, 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 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 [see CLINICAL PHARMACOLOGY (12.3)].
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 [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.2) and CLINICAL PHARMACOLOGY (12.3)].
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 [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.3) and CLINICAL PHARMACOLOGY (12.3)].
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