Index
It acts as an α1 adrenergic receptor antagonist with high uroselectivity (selectivity for the prostate).
Silodosin (trade names Rapaflo (USA), Silodyx (Europe and South Africa), Rapilif (India), Silodal (India), Sildoo (India) Urief (Japan), Thrupas (South Korea), Urorec (Russia) is a medicine for the symptomatic treatment of benign prostatic hyperplasia .
Symptoms associated with lower urinary tract benign prostatic hyperplasia (BPH) (LUTS) are highly prevalent in older men.
Medical therapy is the first-line treatment for lower urinary tract symptoms due to benign prostatic hyperplasia.
Alpha-adrenergic receptor blockers remain a mainstay in the treatment of male lower urinary tract symptoms and clinical benign prostatic hyperplasia.
They show an early onset of efficacy with regard to symptoms and flow rate improvement, and this is clearly demonstrated in placebo-controlled trials with extensions of up to five years.
These agents have been shown to prevent symptomatic progression of the disease.
How is the composition of the drug?
Rapaflo is the brand name for silodosin, a selective alpha-1 adrenergic receptor antagonist. The chemical name for Rapaflo is:
- 1- (3-hydroxypropyl) -5 – [(2R) -2 – ({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2,3-dihydro-1H-indole 7-carboxamide.
The molecular formula is:
- C25H32F3N3O4 with a molecular weight of 495.53.
Silodosin is a white to pale yellow 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 capsule for oral administration contains 8 mg, 4 mg of silodosin and the following inactive ingredients: D-mannitol, magnesium stearate, pregelatinized starch, and sodium lauryl sulfate.
Hard gelatin capsules contain gelatin and titanium dioxide. The capsules are printed with edible ink that contains yellow iron oxide.
Dosage and administration
The recommended dose is 8 mg orally once a day with a meal.
Patients who have difficulty swallowing pills and capsules can carefully open the Rapaflo capsule and sprinkle the powder into a tablespoon of apple sauce.
Applesauce should be swallowed immediately (within 5 minutes) without chewing and followed with an 8-ounce glass of cold water to ensure complete ingestion of the powder.
Any powder / applesauce mix should be used immediately (within 5 minutes) and should not be stored for future use.
Renal insufficiency
Rapaflo is contraindicated in patients with severe renal impairment (CRC <30 ml / min).
In patients with moderate renal impairment (CRC 30-50 ml / min), the dose should be reduced to 4 mg once daily with a meal. No dose adjustment is necessary in patients with mild renal impairment (CRC 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 dose adjustment is necessary in patients with mild or moderate hepatic impairment.
History
Rapaflo (silodosin) received its first marketing approval in Japan in May 2006 under the trade name Urief, which is jointly marketed by Kissei Pharmaceutical Co., Ltd. and Daiichi Sankyo Pharmaceutical Co., Ltd.
Kissei licensed the rights to Rapaflo from the US, Canada and Mexico to Watson Pharmaceuticals, Inc. in 2004.
Rapaflo approved by the Food and Drug Administration (FDA) on October 9, 2008. Rapaflo is marketed under the trade names Rapaflo in the US and Silodyx in Europe.
Pharmacology
Since Rapaflo has a high affinity for the α1A adrenergic receptor, it practically does not cause orthostatic hypotension (unlike other α1 blockers).
On the other hand, high selectivity appears to be the cause of the typical Rapaflo side effect of loss of seminal emission.
As α1A adrenergic receptor antagonists are being investigated as a means of male birth control due to their ability to inhibit ejaculation but not orgasm, a trial was conducted with 15 male volunteers.
While Rapaflo was completely effective in preventing semen release in all subjects, 12 of the 15 patients reported mild orgasm discomfort.
Men also reported the psychosexual side effect of being strongly dissatisfied with their lack of ejaculation.
Pharmacokinetics
The drug Rapaflo is absorbed from the intestine and its pharmacokinetic parameters, that is, the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) increase linearly with the dose.
The bioavailability of Rapaflo is almost 32%, with a volume of distribution of 49.5 L, and Rapaflo is bound to 97% of plasma proteins.
Time to maximum concentration of Rapaflo occurs approximately 2.6 hours after ingestion of the drug.
Food has been shown to be involved in the Rapaflo pharmacokinetic pathway. Therefore, the area under the curve and the maximum concentration decrease by 4% to 49% and by 18% to 43%, respectively, with a moderate calorie / fat meal.
Also, food intake delays time to maximum concentration by about an hour.
Therefore, the Food and Drug Administration recommends taking Rapaflo with meals, ideally in the morning to avoid potential side effects associated with high plasma drug concentrations.
Rapaflo undergoes extensive metabolism involving glucuronidation, alcohol aldehyde dehydrogenase, and oxidative pathways involving cytochrome P450 (CYP) 3A4.
This glucuronide conjugate has been found to have a half life of approximately 24 hours compared to 13.3 hours for Rapaflo and an area under the curve three to four times greater than for the parent compound.
Therefore, Rapaflo and its active metabolite have a long half-life that makes once-daily administration possible. Rapaflo is excreted in the urine (33.5%) and in the feces (54.9%).
Because the prevalence of benign prostatic hyperplasia increases considerably with age, the pharmacokinetics of Rapaflo have been studied in older men (mean age 69 years) compared to young men (mean age 24 years).
Both populations had kidney function within normally accepted limits for age.
The area under the curve and elimination half-life of Rapaflo in elderly patients were approximately 15% and approximately 20% higher, respectively, than values in younger subjects.
Furthermore, no difference in the maximum concentration of Rapaflo was observed between the two groups, demonstrating that the pharmacokinetic profile of Rapaflo does not change in elderly patients compared to younger patients.
Therefore, the standard Rapaflo dose of 8 mg once daily can be used in elderly patients without any titration.
Drug dose studies
A study was conducted in six patients with moderate renal impairment (creatinine clearance 30–50 ml / min) and seven patients with normal renal function.
The results showed that the area under the curve, the maximum concentration and the elimination half-life of Rapaflo were 3.2, 3.1 and 2.0 times greater in patients with moderate renal insufficiency than in controls.
Therefore, an initial dose of one 4 mg capsule per day is required in patients with a creatinine clearance of 30 to 50 ml / min and a dose increase is needed after one week.
When creatinine clearance is> 50 ml / min, no adjustment is necessary.
With regard to hepatic impairment, a study comparing nine patients with moderate hepatic impairment (Child-Pugh score 7–9) and nine subjects with normal liver function showed no difference in the pharmacokinetic profile of Rapaflo.
The recommendations of the Food and Drug Administration are that no dose adjustment is necessary in mild to moderate hepatic impairment (Child-Pugh score 5-9) and that Rapaflo is contraindicated in severe impairment (Child-Pugh score > 10).
Drug interactions
Moderate and strong CYP3A4 inhibitors
Because Rapaflo is metabolized via the CYP3A4 pathway, it is contraindicated in patients taking strong CYP3A4 inhibitors, such as clarithromycin, itraconazole, ketoconazole, and ritonavir.
These drugs increase the serum concentration of Rapaflo and the potential risk of side effects by decreasing or inhibiting the metabolism of Rapaflo or may cause the plasma concentrations of Rapaflo to increase.
Rapaflo 8 mg co-administered with ketoconazole 400 mg has been shown to increase the maximum concentration and the area under the Rapaflo curve by 3.8 and 3.2 times, respectively.
Rapaflo can be co-administered with phosphodiesterase type 5 inhibitors.
Exercise caution and monitor patients for adverse events when administering Rapaflo with moderate CYP3A4 inhibitors.
In fact, an open-label, placebo-controlled crossover study showed minimal reductions in systolic and / or diastolic blood pressure after co-administration of Rapaflo with phosphodiesterase type 5 inhibitors (sildenafil 100 mg or tadalafil 20 mg).
Regarding the interaction with antihypertensive agents, there are still no studies that have rigorously evaluated this problem.
However, it is important to note that approximately one-third of the patients enrolled in the US studies were taking antihypertensive agents.
Analysis of the results showed that patients taking antihypertensive agents and Rapaflo together had more episodes of dizziness than normotensive patients taking Rapaflo alone, as well as a higher frequency of orthostatic hypotension.
Therefore, careful use and careful monitoring must be done, and further clinical studies are mandatory.
Inhibitors of strong P-glycoprotein (P-gp)
In vitro studies indicated that Rapaflo is a substrate for P-gp. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused a significant increase in Rapaflo exposure.
Inhibition of P-gp can lead to an increase in silodosin concentration. Therefore, Rapaflo is not recommended in patients taking strong P-gp inhibitors, such as cyclosporine.
Alpha blockers
Pharmacodynamic interactions between Rapaflo and other alpha blockers have not been determined. However, interactions can be expected and Rapaflo should not be used in combination with other alpha blockers.
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 men, aged 18 to 45 years.
Concomitant administration of Rapaflo and digoxin did not significantly alter the steady-state pharmacokinetics of digoxin.
PDE5 inhibitors
Co-administration of Rapaflo with a single dose of sildenafil 100 mg or tadalafil 20 mg was evaluated in a placebo-controlled clinical study involving 24 healthy male subjects, 45 to 78 years of age.
Orthostatic vital signs were monitored within 12 hours after concomitant administration. During this period, the total number of positive orthostatic test results was higher in the group that received Rapaflo plus a PDE5 inhibitor compared to Rapaflo alone.
No events of orthostasis or symptomatic dizziness were reported in subjects receiving Rapaflo with a PDE5 inhibitor.
Other concomitant drug treatment
Antihypertensive
However, approximately one third of patients in clinical studies used concomitant antihypertensive drugs with Rapaflo.
The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general Rapaflo population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively).
Food interactions
The effect of a moderate fat and calorie meal on Rapaflo pharmacokinetics was variable and decreased Rapaflo maximum plasma concentration (Cmax) by approximately 18 to 43% and exposure (AUC) by 4 to 49% in three different studies. .
Safety and efficacy clinical trials for Rapaflo were always conducted in the presence of food intake.
Precautions
Orthostatic effects
Postural hypotension may develop, with or without symptoms (eg, dizziness) when starting treatment with Rapaflo.
As with other alpha blockers, there is a potential for syncope.
Renal insufficiency
In a clinical pharmacology study, the plasma concentrations (AUC and Cmax) of Rapaflo were approximately three times higher in subjects with moderate renal impairment compared to subjects with normal renal function, while the half-life of Rapaflo doubled.
Pharmacokinetic 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 peak plasma concentrations of Rapaflo and a 3.2-fold increase. times in exposure to Rapaflo (i.e. area under the curve).
Pharmacodynamic drug interactions
Pharmacodynamic interactions between Rapaflo and other alpha blockers have not been determined.
A specific pharmacodynamic interaction study between Rapaflo and antihypertensive agents has not been performed.
Caution is also advised when alpha adrenergic blocking agents, including Rapaflo, are co-administered with PDE5 inhibitors.
Concomitant use of these two classes of drugs can cause symptomatic hypotension.
Intraoperative Iris Floppy Syndrome
Intraoperative floppy iris syndrome has been observed during cataract surgery in some patients with alpha-1 blockers or previously treated with alpha-1 blockers.
Patients planning cataract surgery should be informed to inform their ophthalmologist that they are taking Rapaflo.
Laboratory test interactions
No interactions were observed in laboratory tests during clinical evaluations. Treatment with Rapaflo for up to 52 weeks had no significant effect on prostate specific antigen (PSA).
Non-clinical toxicology
Carcinogenesis, mutagenesis, impaired fertility
In a 2-year oral carcinogenicity study in rats, doses up to 150 mg / kg / day were administered.
Approximately 8 times the maximum recommended human dose exposure (MRHE) based on the area under the Rapaflo curve, an increase in thyroid follicular cell tumor incidence was observed in male rats receiving doses. 150 mg / kg / day.
Rapaflo induced stimulation of thyroid stimulating hormone (HST) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4).
Rapaflo did not alter thyroid stimulating hormone levels or thyroxine levels in clinical trials and no effects were seen based on thyroid exams.
In a 2-year oral carcinogenicity study in mice, doses of up to 100 mg / kg / day were administered to males.
At approximately nine times the maximum recommended human dose based on Rapaflo AUC and 400 mg / kg / day in females (approximately 72 times the maximum recommended human dose based on AUC), there were no significant tumor findings in male mice.
Females treated for 2 years with doses of 150 mg / kg / day (approximately 29 times the maximum recommended human dose based on AUC) or more had statistically significant increases in the incidence of adenoacanthomas and adenocarcinomas of the mammary gland.
The increased incidence of mammary gland neoplasms in female mice was considered secondary to the Rapaflo-induced hyperprolactinemia measured in the treated mice.
Elevated prolactin levels were not observed in clinical trials.
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 pharmacological activity similar to Rapaflo.
Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, the mouse lymphoma assay, the 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 chromosome aberration assays at high and cytotoxic concentrations.
Treatment of male rats with Rapaflo for 15 days resulted in decreased fertility at the high dose.
Undesirable effects
Despite its high uroselectivity, Rapaflo is associated with side effects.
In Japanese and American studies, the most frequently reported adverse reaction was retrograde ejaculation.
Retrograde ejaculation is the result of smooth muscle relaxation in the prostate, urethra, bladder neck, and vas deferens.
Α1A-AR is expressed primarily in the bladder neck, vas deferens, and seminal vesicles. Furthermore, a pharmacological study showed that the α1A-AR subtype mediates contraction of the human vas deferens.
Thus, this adverse reaction is explained by Rapaflo’s high selectivity of the α1A-AR subtype.
The other adverse events commonly associated with Rapaflo were upper respiratory tract infection, thirst, loose stools, urinary incontinence, diarrhea, dizziness, and orthostatic hypotension.
The open-label extension study by Marks et al allowed evaluation of the long-term safety of Rapaflo. Retrograde ejaculation occurred more frequently in patients receiving de novo treatment than in patients continuing treatment.
Orthostatic hypotension occurred in the same range. More patients who received de novo treatment discontinued the study due to retrograde ejaculation than those who continued treatment.
During this extension study, no cardiac disorders or corrected QT prolongation were found with long-term use of Rapaflo.
Intraoperative floppy iris syndrome (IFIS) is a complication of cataract surgery seen in patients who have previously been treated with α1-blockers, primarily tamsulosin.
The clinical manifestations of intraoperative floppy iris syndrome are constriction of the pupil, fluttering and waviness of the iris stroma, with a propensity for iris prolapse during cataract surgery.
A prospective study was conducted in 1968 Japanese patients who received various α1 blockers, including Rapaflo, prior to cataract surgery.
The overall incidence of intraoperative floppy iris syndrome was 1.1% and, interestingly, no intraoperative floppy iris syndrome occurred in patients receiving Rapaflo.
However, one case of intraoperative floppy iris syndrome was reported in a nine-month open-label tolerability study of Rapaflo.
However, patients should inform their ophthalmologist about the use of Rapaflo, and it is recommended to discontinue the medication before performing cataract surgery.
Conclution
Alpha-blockers remain the first-line treatment for lower urinary tract symptoms in benign prostatic hyperplasia.
Rapaflo, a new α1A blocker, has been approved by the Food and Drug Administration since October 2008 at a recommended dose of 8 mg orally once daily.
Clinical studies have shown this selective α1A-AR to be highly attractive and more effective than placebo for voiding and storage symptoms in lower urinary tract symptoms arising from benign prostatic hyperplasia.
Rapaflo has excellent early efficacy, and is at least as effective as other α1-blockers.
Rapaflo is distinguished by a strong effect not only on symptoms, but also on obstruction as measured by pressure flow studies, a finding perhaps explained by its strong selectivity for α1A-AR.
At present, it is still unknown whether combining Rapaflo with 5α-reductase inhibitors is better than either treatment alone in reducing disease progression.
Although Rapaflo is very attractive, a long-term study comparing this drug with other α1 blockers, especially tamsulosin, is needed to help doctors write the correct prescription for the treatment of benign prostatic hyperplasia and tract symptoms. lower urinary in men.
