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Rapaflo Capsules

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Rapaflo Capsules

Rapaflo Capsules

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Orthostatic Effects

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, Use In Specific Populations, CLINICAL PHARMACOLOGY, and PATIENT INFORMATION].

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 and CLINICAL PHARMACOLOGY].

RAPAFLO is contraindicated in patients with severe renal impairment [see CONTRAINDICATIONS].

Hepatic Impairment

RAPAFLO has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients [see CONTRAINDICATIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY].

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].

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].

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 and DRUG INTERACTIONS].

Caution is also advised when alpha-adrenergic blocking agents including RAPAFLO are coadministered 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].

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.

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].

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).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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).

Use In Specific Populations

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.

Pediatric Use

RAPAFLO is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.

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].

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, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

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, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 7/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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