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西罗多辛（silodosin）由Watson公司研制开发，商品名为Rapaflo。该药为胶囊制剂，于2008年10月由美国食品药品管理局批准上市，用于改善良性前列腺增生（benign prostatic hyperplasia，BHP）引起的排尿困难等症状。 【英文别名】1-(3-Hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-dihydro-1H-indole-7-carboxamide 分子式：C25H32F3N3O4分子量：582.65 美国首次批准：2008 RAPAFLO表示，α-1肾上腺素能受体拮抗剂，用于治疗良性前列腺增生症（BPH）的症状和体征。 （1）RAPAFLO还没有表示用于治疗高血压。 警告和注意事项 药物相互作用 日期更新：02/2012 FDA 批准Rapaflo用于改善良性前列腺增生引起的症状 FDA 于2008年10月4日批准Watson 公司 的silodosin胶囊 (Rapaflo) 用于改善良性前列腺增生（也称为前列腺肥大）（BHP）引起的症状。良性前列腺增生在50岁男性中的发病率为50%，在80年男性中的发病率升高至75%。本品通过阻断前列腺、膀胱、输尿管中的肾上腺α1受体而起作用，通过阻断这些受体，使得在这些组织中的平滑肌得以放松，从而减轻前列腺增生的症状。 本品为一日1次的胶囊剂，针对无肝肾功能损伤患者的服用剂量为8mg/天，轻中度肝肾功能损伤患者的服用剂量是4mg/天，本品不推荐在重度肝肾功能损伤的患者中使用。两项纳入923例患者为期12周的随机双盲安慰剂对照的多中心临床研究结果表明：本品与安慰剂相比对BHP症状的改善情况与小便通畅率的改善均有显著的统计学意义。 本品的主要不良反应为在性高潮期间没有精液排除或者精液排除减少。但这一不良反应不会纳入对本品的安全性考虑，其他的不良反应还包括眩晕，头昏，腹泻，体位性高血压，头痛，鼻咽炎，鼻充血等。
Rapaflo FULL PRESCRIBING INFORMATION 1 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) [see Clinical Studies (14)]. RAPAFLO is not indicated for the treatment of hypertension. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose is 8 mg orally once daily with a meal. 2.2 Dosage Adjustment in Special Populations 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) [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 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 [see Contraindications (4), Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 3 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. 4 CONTRAINDICATIONS
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)]. 5.2 Renal Impairment 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)]. 5.3 Hepatic Impairment 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)]. 5.4 Pharmacokinetic Drug-Drug Interactions 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)]. 5.5 Pharmacodynamic Drug-Drug Interactions 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)]. 5.6 Carcinoma of the Prostate 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. 5.7 Intraoperative Floppy Iris Syndrome 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)]. 5.8 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). 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 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. Adverse Reactions observed in at least 2% of patients: 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. 6.2 Postmarketing Experience 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 Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values 7 DRUG INTERACTIONS 7.1 Moderate and Strong CYP3A4 Inhibitors 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. 7.2 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 [see Clinical Pharmacology (12.3)]. 7.3 Alpha-Blockers 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)]. 7.4 Digoxin 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. 7.5 PDE5 Inhibitors 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. 7.6 Other Concomitant Drug Therapy Antihypertensives 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)]. Metabolic Interactions In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems. 7.7 Food Interactions The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18 − 43% and exposure (AUC) by 4 − 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)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 8.4 Pediatric Use RAPAFLO is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use 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)]. 8.6 Renal Impairment 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)]. 8.7 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 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)]. 10 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. 11 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-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide and the molecular formula is C25H32F3N3O4 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. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 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. 12.2 Pharmacodynamics Orthostatic Effects 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 [see Warnings and Precautions (5.1)].
Cardiac Electrophysiology 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) [see Contraindications (4), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 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. 12.3 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 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 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 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. 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 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 Cmax of silodosin was observed [see Use in Specific Populations (8.5)]. 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, 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 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 [see Contraindications (4), Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]. 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 [see Contraindications (4), Warnings and Precautions (5.3) and Use in Specific Populations (8.7)]. Drug Interactions 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 Cmax 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 Cmax 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 In vitro studies indicated that silodosin is a P-gp substrate. A drug interaction study with a strong P-gp inhibitor has not been conducted. However, in drug interaction studies with ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, significant increase in exposure to silodosin was observed (see Clinical Pharmacology, Drug Interactions, CYP3A4 Inhibitors). Inhibition of P-gp may lead to increased silodosin concentration. Silodosin is not recommended in patients taking strong P-gp inhibitors (e.g., cyclosporine). 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 Cmax were observed when digoxin was administered alone or concomitantly with silodosin. Other Metabolic Enzymes and Transporters In vitro studies indicated that silodosin administration is not likely to inhibit the activity of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 or induce the activity of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-gp. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day [about 8 times the exposure of the maximum recommended human dose (MRHE) based on AUC of silodosin], an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of 150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known. In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about nine times the MRHE based on AUC of silodosin) and 400 mg/kg/day in females (about 72 times the MRHE based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the MRHE based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has similar pharmacological activity to silodosin. Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, mouse lymphoma assay, unscheduled DNA synthesis assay and the in vivo mouse micronucleus assay. A weakly positive response was obtained in two in vitro Chinese Hamster Lung (CHL) tests for chromosomal aberration assays at high, cytotoxic concentrations. Treatment of male rats with silodosin for 15 days resulted in decreased fertility at the high dose of 20 mg/kg/day (about twice the MRHE) which was reversible following a two week recovery period. No effect was observed at 6 mg/kg/day. The clinical relevance of this finding is not known. In a fertility study in female rats, the high dose of 20 mg/kg/day (about 1 to 4 times the MRHE) resulted in estrus cycle changes, but no effect on fertility. No effect on the estrus cycle was observed at 6 mg/kg/day. In a male rat fertility study, sperm viability and count were significantly lower after administration of 600 mg/kg/day (about 65 times the MRHE) for one month. Histopathological examination of infertile males revealed changes in the testes and epididymides at 200 mg/kg/day (about 30 times the MRHE). 14 CLINICAL STUDIES 14.1 Benign Prostatic Hyperplasia Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted with 8 mg daily of silodosin. In these two studies, 923 patients [mean age 64.6 years; Caucasian (89.3%), Hispanic (4.9%), Black (3.9%), Asian (1.2%), Other (0.8%)] were randomized and 466 patients received RAPAFLO 8 mg daily. The two studies were identical in design except for the inclusion of pharmacokinetic sampling in Study 1. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure. Mean changes from baseline to last assessment (Week 12) in total IPSS score were statistically significantly greater for groups treated with RAPAFLO than those treated with placebo in both studies (Table 4 and Figures 2 and 3).
B - Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values. B - Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values. Mean IPSS total score for RAPAFLO once daily groups showed a decrease starting at the first scheduled observation and remained decreased through the 12 weeks of treatment in both studies. RAPAFLO produced statistically significant increases in maximum urinary flow rates from baseline to last assessment (Week 12) versus placebo in both studies (Table 5 and Figures 4 and 5). Mean peak flow rate increased starting at the first scheduled observation at Day 1 and remained greater than the baseline flow rate through the 12 weeks of treatment for both studies.
B - Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values. B - Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values. 16 HOW SUPPLIED/STORAGE AND HANDLING White, opaque, hard gelatin 8 mg capsules. 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:
Storage 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. --------------------------------------------------------------- --------------------------------------------------------------- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
西罗多辛胶囊|RAPAFLO(silodosin)capsule简介：
西罗多辛（silodosin）由Watson公司研制开发，商品名为Rapaflo。该药为胶囊制剂，于2008年10月由美国食品药品管理局批准上市，用于改善良性前列腺增生（benign prostatic hyperplasia，BHP）引起的排尿 ... 责任编辑：admin |
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