Rapaflo
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Rapaflo - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Benign Prostatic Hyperplasia
Class: Antiadrenergic agents, peripherally acting
Form: Capsules
Ingredients: Silodosin, D-mannitol, Magnesium Stearate, Pregelatinized Starch, And Sodium Lauryl Sulfate. The Size #1 And #3 Hard Gelatin Capsules Contain Gelatin And Titanium Dioxide. The #1 Capsules Are Printed With Edible Ink Containing Fdandc Blue No. 1 Aluminum Lake And Yellow Iron Oxide. The #3 Capsules Are Printed With Edible Ink Containing Yellow Iron Oxide.

Pharmaceutical information

Drug Substance

Common Name: silodosin
Chemical name: (-)-1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide.
Molecular formula and molecular mass: C25H32F3N3O4; 495.53

Structural formula:

Physiochemical properties: 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.

Clinical trials

Study Demographic and Trial Design

Benign Prostatic Hyperplasia (BPH):

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 (silodosin) 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.

Study Results

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 1 and Figure 1 and Figure 2).

Table 1 Mean Change from Baseline in International Prostate Symptom Score (IPSS) in Two Randomized, Controlled, Double-Blind Studies
Total Symptom
Score
Study 1 Study 2
RAPAFLO
8 mg
(n=233)
Placebo
(n=228)
p-value RAPAFLO
8 mg
(n=233)
Placebo
(n=229)
p-value
Baseline 21.5(5.38) 21.4(4.91) 21.2(4.88) 21.2(4.92)
3 to 4 Day Change From Baseline -3.9(5.40) -2.0(4.34) <0.0001 -4.4(5.12) -2.5(4.39) <0.0001
Week 12 / LOCF Change from Baseline -6.5(6.73) -3.6(5.85) <0.0001 -6.3(6.54) -3.4(5.83) <0.0001

LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.

Figure 1 Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 1


B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.


Figure 2 Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 2


B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.


RAPAFLO produced highly significant reductions (p < 0.0001) of total IPSS scores at all time points in the studies, demonstrating both rapid (within 3 to 4 days) and sustained positive effects.

RAPAFLO produced significant, rapid, and sustained reductions in both irritative and obstructive symptoms as measured by the change from baseline in the appropriate IPSS subscales. Table 2 and Table 3 present IPSS irritative and obstructive subscale results.

Table 2 Mean Change (SD) from Baseline in the IPSS Irritative Symptoms Subscale in Two Randomized, Controlled, Double-Blind Studies
Irritative Symptom
Score
Study 1 Study 2
RAPAFLO
8 mg
(n = 233)
Placebo
(n = 228)
p-value RAPAFLO
8 mg
(n = 233)
Placebo
(n = 229)
p-value
Baseline 9.5(2.56) 9.4(2.44) 9.2(2.62) 9.2(2.59)
3 to 4 Day Change from Baseline -1.3(2.42) -0.8(2.17) 0.0192 -1.5(2.29) -0.9(2.15) 0.0033
Week 12 / LOCF Change from Baseline -2.3(2.97) -1.4(2.70) 0.0004 -2.4(2.89) -1.3(2.62) 0.0001

LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.


Table 3 Mean Change (SD) from Baseline in the IPSS Obstructive Symptoms Subscale in Two Randomized, Controlled, Double-Blind Studies
Obstructive
Symptom Score
Study 1 Study 2
RAPAFLO
8 mg
(n=233)
Placebo
(n=228)
p-value RAPAFLO
8 mg
(n=233)
Placebo
(n=229)
p-value
Baseline 12.0(3.85) 12.0(3.57) 12.0(3.26) 11.9(3.49)
3 to 4 Day Change from Baseline -2.6(3.57) -1.2(2.91) <0.0001 -2.9(3.53) -1.6(3.06) <0.0001
Week 12 / LOCF Change from Baseline -4.2(4.32) -2.2(3.75) <0.0001 -3.9(4.31) -2.1(3.77) <0.0001

LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.

RAPAFLO produced rapid and significant increases in maximum urinary flow rates from baseline to last assessment versus placebo in both studies (Table 4 and Figure 3 and Figure 4). Statistically significant treatment effects on maximum urine flow rates were noted within 2 to 6 hours after the first dose and at the end of both Study 1 and 2.

Table 4 Mean Change (SD) from Baseline in Maximum Urinary Flow Rate (mL/sec) in Two Randomized, Controlled, Double-Blind Studies
Mean Maximum
Flow Rate
(mL/sec)
Study 1 Study 2
RAPAFLO
8 mg
(n=233)
Placebo
(n=228)
p-value RAPAFLO
8 mg
(n=233)
Placebo
(n=229)
p-value
Baseline 9.0(2.60) 9.0(2.85) 8.4(2.48) 8.7(2.67)
2 to 6 Hours Change from Baseline 2.7(3.48) 0.8(3.05) <0.0001 2.9(3.41) 2.1(4.26) 0.0494
Week 12 / LOCF Change from Baseline 2.2(4.31) 1.2(3.81) 0.0060 2.9(4.53) 1.9(4.82) 0.0431

LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.

Figure 3 Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 1


B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.
Note – The first Qmax assessments at Day 1 were taken 2-6 hours after patients received the first dose of double- blind medication.
Note – Measurements at each visit were scheduled 2-6 hours after dosing (approximate peak plasma silodosin concentration).


Figure 4 Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 2


B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.
Note – The first Qmax assessments at Day 1 were taken 2-6 hours after patients received the first dose of double- blind medication.
Note – Measurements at each visit were scheduled 2-6 hours after dosing (approximate peak plasma silodosin concentration).


RAPAFLO had positive effects on quality of life based on the IPSS Quality of Life subscale, as measured at various intervals during dosing. The RAPAFLO treatment effects exceeded treatment effects of placebo. The percentage of RAPAFLO patients reporting to be in the delighted, pleased, mostly satisfied, and mixed categories increased from 6.9% to 32%, whereas the percentage of placebo patients using these descriptors increased from 7.2% to 22.5%.

Table 5 Summary of Quality of Life Related to Urinary Symptoms in Two Randomized, Controlled, Double-Blind Studies
IPSS Question 8 Responses Treatment, n (%)
Silodosin (n = 466) Placebo (n = 457)
Baseline
   Delighted, pleased, or mostly satisfied
   Mixed about equally satisfied and dissatisfied
   Mostly dissatisfied, unhappy, or terrible

32(6.9)
126(27.0)
308(66.1)

33(7.2)
124(27.1)
300(65.6)
Week 12 (LOCF)
   Delighted, pleased, or mostly satisfied
   Mixed about equally satisfied and dissatisfied
   Mostly dissatisfied, unhappy, or terrible

149(32.0)
141(30.3)
176(37.3)

103(22.5)
110(24.1)
244(53.4)

LOCF – Last observation carried forward for those not providing data at 12 weeks of treatment.


Long Term Treatment of BPH

Patients in Studies 1 and 2 who received either RAPAFLO or placebo were allowed to continue in a 40-week open-label extension study. Patients who received RAPAFLO in the double-blind period continued to see improvements in total IPSS as well as irritative and obstructive symptoms for up to 1 year of treatment; total IPSS score decreased by an additional 1.6 in these patients. Figure 5 provides results for all patients in the open-label extension study.

Figure 5 Mean Change (SD) from Baseline (End of Double-Blind Studies) to Week 40 in IPSS Total Score and Subscores in Open-Label Extension Study (Evaluable Population, N = 429)


Detailed pharmacology

Silodosin has high affinity for α1A-Adrenergic Receptor (α1A-AR) subtype (pKi value: 10.4). The selectivity of silodosin for α1A-AR subtype was 162 times and 55.0 times higher than for subtypes α1B-AR and α1D-AR, respectively. In addition, the selectivity of silodosin for subtype α1A-AR was the highest among other α1-AR blockers, including tamsulosin hydrochloride, prazosin hydrochloride, and terazosin hydrochloride. Silodosin had a strong inhibitory effect on contraction induced by treatment with noradrenalin in the lower urinary tract organs such as the prostate, the urethra and the trigone of the urinary bladder on which subtype α1A-ARs are predominantly located (the pA2 or pKb value: 9.60, 8.71 and 9.35, respectively). The pA2 values of the inhibitory effect on contraction induced by treatment with noradrenalin in the isolated spleen of rats on which α1B-AR subtype is predominantly located, and in isolated thoracic aortas in rats on which α1D-AR is predominantly located, were 7.15 and 7.88, respectively. The receptor binding study and the function study using isolated organs revealed that silodosin had higher selectivity for α1A-AR subtype of the lower urinary tract organs compared to the other α1- AR blockers.

In human plasma two major metabolites of silodosin (those greater than 10 percent of parent drug systemic exposure at steady state) were identified and designated KMD-3213G and KMD-3293. The glucuronide conjugate of silodosin, KMD-3213G, which is not detected in animal plasma, had 1/8 times the affinity of silodosin for human α1-AR. In animals, this human metabolite had 1/4.5 times the affinity for α1A-AR subtype in rats, about 1/2 the inhibitory effect on contraction induced by noradrenalin in the isolated prostate in rats, and not greater than 1/10 the transferability to the prostate of silodosin. KMD-3293, the other major metabolite of silodosin in humans, was detected in animal plasma and had 1/42 times the affinity of silodosin for subtype α1A-AR in humans.

A rat model of benign prostatic hyperplasia, prepared by administering sex hormones, had overactive bladder-like contractions when urine accumulated in the body. Silodosin significantly inhibited the number of overactive cytoid contractions. In secondary pharmacodynamic studies, silodosin had comparatively high binding affinities for β2-AR as well as α1-ARs, but inhibited β2-AR in the isolated uterus in pregnant rats at a higher concentration than the concentration at which silodosin inhibited α1-ARs in the prostate. Furthermore, silodosin had low affinities for other types of receptors except for β2-AR, and accordingly was less likely to exhibit any effects through receptor types other than α1-ARs in clinical use.

The safety pharmacology studies of silodosin revealed minimally significant effects on the central nervous system or on the respiratory system. With regard to the cardiovascular system, a decrease in blood pressure of about 20% of the baseline values was seen in conscious dogs after oral administration of silodosin at 20 mg/kg,(1) but silodosin had no effect on heart rate and electrocardiography in conscious dogs. Silodosin also inhibited hERG current at high concentrations and prolonged APD90 in the myocardial action potential in isolated papillary muscle from guinea pigs. However, these effective concentrations (4,415 ng/mL) are about 72- fold higher than 61.6 ng/mL, the maximum concentration of silodosin in healthy adult human males receiving repeat oral administration of 8 mg, which is the recommended clinical dose. Thus, silodosin is expected to have little effect on the repolarization in the heart. In a thorough QT electrocardiography study, silodosin capsules 8 mg daily, silodosin capsules 24 mg daily, placebo daily, or a single dose of moxifloxacin 400 mg were administered to healthy male humans. Silodosin capsules 8 mg and 24 mg daily had no statistically significant effect on ECG intervals or cardiac repolarization relative to placebo. Furthermore, there was no dose-response relationship observed with the product.

The main plasma metabolite of silodosin is a glucuronide conjugate (KMD-3213G) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). The second major plasma metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin. KMD-3213G, which is not detected in animal plasma, had 1/8 times the affinity of silodosin for human α1-AR. In animals, this human metabolite had 1/4.5 times the affinity for α1A-AR subtype in rats, about 1/2 the inhibitory effect on contraction induced by noradrenalin in the isolated prostate in rats, and not greater than 1/10 the transferability of silodosin to the prostate. The safety pharmacology studies in which KMD-3213G was intravenously injected revealed that KMD-3213G had no meaningful effects on the central nervous system, the respiratory system, or the cardiovascular system.

Metabolite KMD-3293 was detected in animal plasma and had 1/42 times the affinity of silodosin for subtype α1A-AR in humans.

Toxicology

Acute Toxicity

A single oral administration study in rats revealed that the approximate lethal dose was 800 mg/kg for males and females. The approximate lethal doses for male and female rats receiving an intravenous administration were 75 mg/kg and 90 mg/kg, respectively. The single administration study in dogs disclosed that the approximate lethal dose was 1500 mg/kg for orally administered silodosin and 50 mg/kg or more via intravenous injection.

Table 6 Single Dose Toxicity Studies in Rats and Dogs after Oral and Intravenous Administration
Species Route Doses (mg/kg)
Rats oral
oral
500, 1000, 2000
400, 800, 1600
I.V. 0, 60, 75, 90
Dogs oral
oral
1500, 2000
1000, 1500
I.V. 25, 50

Chronic Toxicity

A 1-month administration study in rats revealed fatty degeneration in liver hepatocytes given 60 mg/kg/day or more, and the no observed adverse effect level (NOAEL) of silodosin was estimated at 20 mg/kg/day. A 3-month repeat oral administration study in rats revealed moderate to severe fatty degeneration of hepatocytes and hypertrophy and eosinophilic changes of centrilobular hepatocytes in the males receiving 100 mg/kg/day or more, and hypertrophy of centrilobular hepatocytes in females receiving 400 mg/kg/day or more. The NOAEL of silodosin was estimated to be 25 mg/kg/day in males and 100 mg/kg/day in females. A 26-week oral administration study in rats showed fatty degeneration of hepatocytes in males receiving 15 mg/kg/day or more and in females given 300 mg/kg/day. Males receiving 5 mg/kg/day showed only a mild fatty degeneration of hepatocytes, which was also seen in the control group. The NOAEL of silodosin was estimated to be 5 mg/kg/day. In a 2-week intravenous injection study in rats, mortality was noted in the 50 mg/kg/day group, and the NOAEL of silodosin was estimated to be 10 mg/kg/day.

Following a 28-day administration in rats, plasma evaluations revealed decreased throxine (T4) levels at all dosage levels (50-300 mg/kg/day), increased thyroid stimulating hormone (TSH) at 150 and 300 mg/kg/day, and decreased triiodothyronine (T3) at 300 mg/kg/day. Liver to body weight ratio was increased at 150 and 300 mg/kg/day, along with thyroid/parathyroid to body weight ratio in the 300 mg/kg/day group. Histopathological examination revealed centrilobular hepatocellular hypertrophy and hypertrophy of the thyroid follicular epithelium at 150 and 300 mg/kg/day. Increased hepatic microsomal T4-UDP-GT activity was observed in the 300 mg/kg/day group. Changes in the CYP-dependent enzyme activities also occurred. Most notable were the significant increases in CYP1A at all dosage levels, increases in CYP3A in the 150 and 300 mg/kg/day groups, increases in CYP2B in the 300 mg/kg/day group, and increases in lauric acid 11-hydroxylase and lauric acid 12-hydroxylase in the 150 and 300 mg/kg/day groups.

A 1-month oral administration study in dogs showed degeneration of the seminiferous tubular epithelium in animals receiving 25 mg/kg/day or more, with the NOAEL of silodosin estimated to be less than 25 mg/kg/day. A 13-week oral administration study in dogs revealed decreased body weights in both males and females in the 50 mg/kg/day group, and atrophy of the thymus and retarded maturation of the genitalia in males given 50 mg/kg/day. The NOAEL of silodosin was estimated to be 10 mg/kg/day. A 52-week oral administration study showed decreases in body weight, erythrocyte count, hemoglobin level, and hematocrit level in dogs given 80 mg/kg/day. The NOAEL of silodosin was estimated to be 20 mg/kg/day. A 2-week intravenous administration study revealed no marked changes, and the NOAEL of silodosin was estimated at 25 mg/kg/day.

Table 7 Chronic Dose Toxicity Studies in Rats and Dogs after Oral and Intravenous Administration
Species Route Duration of Dosing Doses (mg/kg)
Rat oral 28 days
1 month
1 month
3 months
26 weeks
26 weeks
0, 50, 150, 300
0, 30, 100, 300, 800
0, 20, 60, 200, 600
0, 25, 100, 400
0, 15, 60, 300
0, 1, 5
I.V. 2 weeks 0, 2, 10, 50
Dog oral 2 weeks
1 month
13 weeks
52 weeks
50, 200, 500
0, 25, 100, 400
0, 10, 50, 100/200
0, 5, 20, 80
I.V. 2 weeks 0, 1, 5, 25

Mutagenicity Studies

The reverse mutation assay in bacteria, the mouse lymphoma assay, the micronucleus test in mice, and the unscheduled DNA synthesis (UDS) test with rat hepatocytes revealed no genotoxicity potential for silodosin. A positive response was noted in the in vitro chromosomal aberration assay with Chinese hamster culture cells. This positive response was noted only at high levels in which cytotoxicity was noted. Silodosin did not induce chromosome aberrations in the in vivo genotoxicity study conducted when animals were exposed to the drug. Silodosin and its metabolites are not considered genotoxic.

Carcinogenicity Studies

In a 2-year carcinogenicity study, male mice were administered silodosin at 20, 60, and 100/200 mg/kg/day and female mice were administered 60, 150, and 400 mg/kg/day. Decreased body weights were observed at 200 mg/kg/day in males; therefore, the highest dosage was decreased to 100 mg/kg/day at Week 27 of administration. Mammary tumors and pituitary adenomas were observed in females treated at 150 mg/kg/day or higher and females treated at 400 mg/kg/day, respectively. The finding of pituitary adenomas was not statistically significant relative to controls in this study.

In a separate study conducted to elucidate the mechanism of onset of these increases in tumors, mice were administered oral doses of silodosin. Results confirmed increases in blood prolactin levels in the females receiving a single administration of 60 mg/kg/day or more and in females receiving repeat administration of 200 mg/kg/day or more. The mechanism of induction of pituitary and mammary tumors in rodents has been documented in publications as being due to the long-term, excessive stimulation by increased prolactin production and secretion from the pituitary, resulting from suppression of dopamine in the hypothalamus.(2) Accordingly, increased mammary gland and pituitary tumors were considered to be induced by the same mechanism as described above. Non-neoplastic lesions such as an increase in hyperplasia of mammary glands in mice receiving 150 mg/kg/day or more, hyperplasia and hypertrophy of the anterior pituitary, and increases in acinus of the breast and enlarged mammary ducts in mice given 400 mg/kg/day may also be induced by increased production of prolactin and excessive stimulation to the mammary glands. Since prolactin, as well as estrogen and progesterone, accelerates adenomyosis of the uterus in mice,(3) the increase in adenomyosis of the uterus in the female mice receiving 60 mg/kg/day or more may also be induced by increased blood prolactin levels. In addition, since prolactin stimulates corpus luteal function and increases the synthesis of progesterone as described above, increases in cystic uterine glands in the uterus of mice receiving 150 mg/kg/day or more and enlargement of uterine glands in mice given 400 mg/kg/day, may result from the increased secretion of the uterine gland caused by increased progesterone. It is believed that epidemiologic examination in humans revealed that a risk of mammary gland tumors increases with increased blood prolactin in women.(4)

Increases in mammary gland and pituitary tumors in mice are not considered to be significant for the safety of silodosin in humans for the following reasons: repeated doses in mice of 60 mg/kg did not produce an increase in mammary tumors, and doses of 20 mg/kg did not produce an increase in prolactin levels in the blood. The 150 mg/kg/day dose is 125-fold greater, or more, on a mg/kg/day basis, than the recommended human clinical dose. Increases in prolactin levels have also been reported to be increased by AR blockers for dopamine and include the AR blockers tamsulosin and prazosin. Therefore, these data indicate that silodosin caused a significant increase in mammary tumors at 150 and 400 mg/kg via an indirect or secondary mechanism involving increases in prolactin levels that also produced non-significant increases in pituitary and hepatocellular adenomas. Tamsulosin, likewise, has induced significant increases in mammary tumors via a secondary mechanism involving hyperprolactinemia.(5) The mammary tumors noted are likely a class effect, for which there is no evidence of clinical relevance.

In the rat carcinogenicity study in which males were administered silodosin at 15, 50, and 150 mg/kg/day, and female rats received 15, 80, and 250 mg/kg/day; follicular cell adenomas of the thyroid were seen only in males of the 150 mg/kg/day group.

A repeat oral administration study in rats conducted to elucidate the possible mechanism of onset of increases in thyroid tumors revealed an increase in the liver UDP-GT activity in males receiving 150 mg/kg/day or more. A similar increase was noted in phenobarbital treated male rats. UDP-GT is involved in the metabolism and excretion of thyroid hormones. An increased UDP-GT activity enhances the catabolism of the thyroid hormones T3 and T4. The catabolism accelerates the secretion of TSH from the pituitary through an inhibition of the negative feedback mechanism. It is also known that since thyroid hormone binding protein is decreased due to catabolism, increases in unbound and free thyroid hormone occur in rats. Thus, the half-life of thyroid hormones is much shorter in rats compared to that of other species including humans.(6,7) Accordingly, the increased catabolism of thyroid hormones quickly decreases thyroid hormone levels in the blood, and the secretion of TSH is consequently increased. Thyroid tumor induction by this indirect mechanism occurs in rats more frequently than in mice, and in males more frequently than in females.(6,7) In contrast, it has been reported that thyroid tumors are not induced by this mechanism in humans.(6,7) Therefore, the neoplastic changes in the thyroid observed in the rat carcinogenicity study are considered secondary to a rat-specific, indirect mechanism, and therefore do not pose a risk to humans for the following reasons: the neoplastic changes in the thyroid are induced by the change in the catabolism of thyroid hormones by the indirect mechanism of thyroid tumor induction as previously described,(8) and there is a sufficient safety margin (72-fold) in dosage between the recommended clinical dose and 50 mg/kg/day in which follicular cell adenomas in the thyroid were not induced in male rats. Other drugs and chemicals have induced thyroid tumors in rats by a similar mechanism (9,10) and have been approved for use.

Reproduction and Teratogenicity Studies

In a study of fertility and early embryonic development and implantation in rats, it was determined that the fertility index decreased due to changes in males, and the mating index decreased due to changes in females. The NOAEL was 6 mg/kg/day for the general toxicity in males and females and 6 mg/kg/day and 20 mg/kg/day for the reproductive function and early embryonic development in males and females, respectively. No teratogenic effects were noted in either rats or rabbits in the study. The NOAEL of silodosin for reproductive function and embryo-fetal development was 1000 mg/kg/day in rats and 60 mg/kg/day in rabbits. In a study for effects on pre- and post-natal development, including maternal function in rats, the NOAEL of silodosin was 30 mg/kg/day for maternal function and 300 mg/kg/day for offspring (F1).

Other Toxicology Studies

In a local irritation study conducted using silodosin injections (0.2 mg/mL, pH 7.15) which were to be used in the clinical pharmacology study (BA / effect of diets), no significant muscle damage in rabbits and no human blood hemolysis were observed.

An antigenicity study confirmed that silodosin demonstrated no antigenic potential in mice or guinea pigs.

An in vitro phototoxicity study showed that silodosin produced mild phototoxicity when exposed to Balb/c 3T3 fibroblast cells in vitro. Treatment with silodosin resulted in a decrease in cell survival in the presence of UV-A light, which was illustrated by a decreased uptake of neutral red. An in vivo phototoxicity study exposing Crl:SKH1-hr hairless mice to UVR radiation from a xenon lamp after a single dose of silodosin was conducted. At the highest dosages of 500 mg/kg in male mice and 400 mg/kg in female mice, the mice exhibited mild, transient erythema indicative of phototoxicity. At lower dosages of 0 (Vehicle), 20, and 100 mg/kg in male mice and 0 (Vehicle), 60, and 150 mg/kg in female mice, no skin events indicative of phototoxicity were noted. The NOAEL in male mice was 100 mg/kg and the NOAEL in female mice was 150 mg/kg, which are much greater than the human clinical dose of 0.11 mg/kg.