SILOFAST D Tablets

Silodosin and Dutasteride

Prescribing information

For the use of Urologist only.

Qualitative and Quantitative Composition

SILOFAST D 4

Each uncoated bilayer tablet contains:

Silodosin .............................. 4mg

Dutasteride IP....................... 0.5 mg

SILOFAST D 8

Each uncoated bilayer tablet contains:

Silodosin .............................. 8mg

Dutasteride IP....................... 0.5 mg

Dosage Form(s) and Strength(s)

Tablet containing silodosin/dutasteride 4/0.5 mg and 8/0.5 mg.

Clinical Particulars

Therapeutic Indications

SILOFAST D bilayer tablets are indicated for the treatment of the signs and symptoms of BPH in men with an enlarged prostate.

They are not intended for use as an antihypertensive drug and is not approved for the prevention of prostate cancer.

Posology and Method of Administration

One bilayer tablet should be taken after meals. The tablet should be swallowed whole.

Contraindications

Silodosin is contraindicated for use in the following:

Severe renal impairment (CCr <30 mL/min)
Severe hepatic impairment (Child-Pugh score ≥10)
Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir)
Patients with a history of hypersensitivity to silodosin or any of the ingredients of the tablet

Dutasteride is contraindicated for use in the following:

Pregnancy: In animal reproduction and developmental toxicity studies, dutasteride inhibited development of the external genitalia of the male foetus. Therefore, dutasteride may cause foetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the foetus.
Women of childbearing potential.
Paediatric patients.
Patients with previously demonstrated clinically significant hypersensitivity (e.g. serious skin reactions, angio-oedema) to dutasteride or other 5 alpha-reductase inhibitors.

Special Warnings and Precautions for Use

Silodosin

Orthostatic Effects

Postural hypotension, with or without symptoms (e.g. dizziness) may develop when beginning silodosin 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.

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 silodosin to rule out the presence of carcinoma of the prostate.

Renal Impairment

In a clinical pharmacology study, plasma concentrations (AUC and C_max) 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 Silodosin should be reduced to 4 mg in patients with moderate renal impairment. Exercise caution and monitor such patients for adverse events.

Silodosin is contraindicated in patients with severe renal impairment.

Hepatic Impairment

Silodosin has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome has been observed during cataract surgery in some patients on alpha₁-blockers or previously treated with alpha₁-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 pre-operative dilation with standard mydriatic drugs; and potential prolapse of the iris toward the phacoemulsification incisions. Patients planning cataract surgery should be advised to inform their ophthalmologist that they are taking silodosin.

Laboratory Test Interactions

No laboratory test interactions were observed during clinical evaluations. Treatment with silodosin for up to 52 weeks had no significant effect on the prostate-specific antigen (PSA).

Pharmacokinetic Drug-Drug Interactions

In a drug interaction study, co-administration of a single 8 mg dose of Silodosin 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.

Pharmacodynamic Drug-Drug Interactions

The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and Silodosin should not be used in combination with other alpha-blockers.

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 Silodosin 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.

Caution is also advised when alpha-adrenergic blocking agents including Silodosin 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.

Dutasteride

Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

In clinical studies, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results.

To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary.

Increased Risk of High-grade Prostate Cancer

In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL, who were taking dutasteride for prevention of prostate cancer in the 4-year trial, there was an increased incidence of Gleason score 8–10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%). In a 7-year, placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg), similar results for Gleason score 8–10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

The 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.

Evaluation for Other Urological Diseases

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out prostate cancer and other, urological diseases prior to treatment with dutasteride and periodically thereafter.

Effects on PSA and the Use of PSA in Prostate Cancer Detection

In clinical studies, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect the PSA test results.

To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent-free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent-free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary.

Co-administration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy.

Exposure of Women — Risk to the Male Foetus

Dutasteride tablet should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended foetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with tablet containing dutasteride, the contact area should be washed immediately with soap and water.

Blood Donation

Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

Effect on Semen Characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy men throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, compared with placebo, dutasteride treatment resulted in mean reduction in total sperm count, semen volume, and sperm motility; the effects on total sperm count were not reversible after 24 weeks of follow-up. Sperm concentration and sperm morphology were unaffected and mean values for all semen parameters remained within the normal range at all timepoints. The clinical significance of the effect of dutasteride on semen characteristics for an individual patient’s fertility is not known.The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 years (n=27 dutasteride, n=23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume and sperm motility were 23%, 26% and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all-time points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride's effect on semen characteristics for an individual patient's fertility is not known.

Drug Interactions

Silodosin

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 silodosin is contraindicated.

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 a 3.8-fold increase in the silodosin C_maxand a 3.2-fold increase in the AUC. Co-administration of 4 mg silodosin with 200 mg ketoconazole led to similar increases: 3.7- and 2.9-fold in the silodosin C_max 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. Concomitant administration with moderate CYP3A4 inhibitors (e.g. diltiazem, erythromycin, verapamil) may increase the concentration of silodosin. Exercise caution and monitor patients for adverse events when co-administering silodosin with moderate CYP3A4 inhibitors..particularly those that also inhibit P-glycoprotein (e.g. verapamil, erythromycin).

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. Silodosin is not recommended in patients taking strong P-gp inhibitors such as cyclosporine.

Alpha-Blockers

The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected and silodosin should not be used in combination with other alpha-blockers.

Digoxin

The effect of co-administration of silodosin and digoxin 0.25mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of silodosin and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required.

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 C_max were observed when digoxin was administered alone or concomitantly with silodosin.

PDE5 Inhibitors

Co-administration of silodosin 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 silodosin plus a PDE5 inhibitor compared with silodosin alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin with a PDE5 inhibitor.

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 silodosin. 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). Caution should be exercised during concomitant use with antihypertensives and patients should be monitored for possible adverse events.

Metabolic Interactions: In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.

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.

Food Interactions

The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (C_max) by approximately 18 to 43% and exposure (AUC) by 4 to 49% across three different studies. Safety and efficacy clinical trials for silodosin 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.

Dutasteride

Cytochrome P450 3A Inhibitors

Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin. Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human CYP450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.

Alpha-Adrenergic Antagonists

The administration of dutasteride in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated. In a single-sequence, crossover study in healthy volunteers, the administration of tamsulosin or terazosin in combination with dutasteride had no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for dutasteride alone compared with the combination treatment.

Calcium Channel Antagonists

Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when co-administered with the CYP3A4 inhibitors verapamil (37%, n=6) and diltiazem (44%, n=5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was co-administered with dutasteride (+7%, n=4).

The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended.

Cholestyramine

Administration of a single 5 mg dose of dutasteride followed 1 hour later by 12 g cholestyramine does not affect the relative bioavailability of dutasteridein 12 normal volunteers.

Digoxin

In a trial of 20 healthy volunteers, dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.

Warfarin

In a trial of 23 healthy volunteers, 3 weeks of treatment with dutasteride 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin.

Other Concomitant Therapy

Although specific interaction trials were not performed with other compounds, approximately 90% of the subjects in the three randomized, double-blind, placebo-controlled safety and efficacy trials receiving dutasteride were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of dutasteride and concurrent therapy when dutasteride was co-administered with anti-hyperlipidaemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.

Use in Special Populations

Patients with Renal Impairment

Silodosin

No dosage adjustment is needed in patients with mild renal impairment (CCr 50 to 80 mL/min)

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.

Silodosin should be reduced to 4 mg per day in patients with moderate renal impairment (CCr: 30 to 50 mL/min). Exercise caution and monitor patients for adverse events.

Silodosin has not been studied in patients with severe renal impairment. Silodosin is contraindicated in patients with severe renal impairment(CCr <30 mL/min).

Dutasteride

No dose adjustment is necessary for dutasteride in patients with renal impairment

Patients with Hepatic Impairment

Silodosin

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.

Silodosin has not been studied in patients with severe hepatic impairment. Silodosin is contraindicated in patients with severe hepatic impairment

Dutasteride

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg.

Pregnant Women

Silodosin

Silodosin is not indicated for use in women.

Dutasteride

Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy.

Dutasteride is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to DHT, a hormone necessary for the normal development of male genitalia

Abnormalities in the genitalia of male foetuses are an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily.

Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats.

Dutasteride is absorbed through the skin. To avoid potential foetal exposure, women who are pregnant or may become pregnant should not handle dutasteride tablet. If contact is made with tablet, the contact area should be washed immediately with soap and water. Dutasteride is secreted into male semen.

The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50 kg woman to 5 mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.175 ng/mL. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein-bound in human semen (>96%), which may reduce the amount of dutasteride available for vaginal absorption.

In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day, with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day. In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days 6 to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity.

In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50-kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption. The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

In an oral pre-and post-natal development study in rats, feminization of the male genitalia was observed. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with a lack of a no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with a no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, a decrease in time to vaginal patency for female offspring, and a decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]).

Lactating Women

SILOFAST D tablet is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride is excreted in human milk.

Paediatric Patients

Silodosin

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

Dutasteride

Dutasteride is contraindicated for use in pediatric patients. Safety and effectiveness in 301 pediatric patients have not been established.

Geriatric Patients

Silodosin

In double-blind, placebo-controlled, 12-week clinical studies of silodosin, 259 (55.6%) patients were below 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 silodosin patients less than 65 years of age (1.2% for placebo), 2.9% of silodosin patients 65 years of age and over (1.9% for placebo), and 5.0% of patients 75 years of age and over (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients.

Dutasteride

Of 2,167 male subjects treated with dutasteride in three clinical trials, 60% were aged 65 years and older and 15% were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Females and Males of Reproductive Potential

Infertility

Silodosin

Males

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

Dutasteride

The clinical significance of dutasteride's effect on semen characteristics for an individual patient's fertility is not known.

Effects on Ability to Drive and Use Machines

Postural hypotension, with or without symptoms (e.g., dizziness) may develop with SILOFAST D therapy. Patients should be cautioned about driving, operating machinery, or performing hazardous tasks when initiating therapy

Undesirable Effects

Silodosin

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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 silodosin 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 silodosin and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of silodosin-treated patients (36.8% for placebo-treated). The majority (72.1%) of adverse reactions for the silodosin-treated patients (59.8% for placebo-treated) were qualified by the investigator as mild. A total of 6.4% of silodosin-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 silodosin-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, multicentre, double-blind, placebo-controlled clinical studies of silodosin 8 mg daily in BPH patients. Adverse reactions that occurred in at least 2% of patients treated with silodosin 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

Silodosin

N=466

n (%)

Placebo

N=457

n (%)

Retrograde ejaculation

131 (28.1)

4 (0.9)

Dizziness

15 (3.2)

5 (1.1)

Diarrhoea

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 above clinical trials, the following adverse events were also reported by between 1% and 2% of patients receiving silodosin and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia and rhinorrhoea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the silodosin treatment group.

In a 9-month open-label safety study of silodosin, one case of intraoperative floppy iris syndrome was reported.

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, 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 oedema, resulting in serious outcomes.

Dutasteride

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 with rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders.

Study withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to study withdrawal was impotence (1%).

Monotherapy

Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5 mg daily doses of dutasteride in three identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year, open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were Caucasian. Table 4 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo.

Table 2: Adverse Reactions Reported in ≥1% of Subjects Over a 24-Month Period and More Frequently in the Group Receiving Dutasteride than the Placebo Group (Randomized, Double-Blind, Placebo-Controlled Studies Pooled) by Time of Onset

Adverse

Reaction

Dutasteride (n)

Placebo (n)

Adverse Reaction Time of Onset

Months 0 to 6

(n=2,167)

(n=2,158)

Months 7 to 12

(n=1,901)

(n=1,922)

Months 13 to 18

(n=1,725)

(n=1,714)

Months 19 to 24

(n=1,605)

(n=1,555)

Impotence^a

Dutasteride

Placebo

4.7%

1.7%

1.4%

1.5%

1.0%

0.5%

0.8%

0.9%

Decreased libido^a

Dutasteride

Placebo

3.0%

1.4%

0.7%

0.6%

0.3%

0.2%

0.3%

0.1%

Ejaculation disorders^a

Dutasteride

Placebo

1.4%

0.5%

0.3%

0.5%

0.1%

0.0%

Breast disorders^b

Dutasteride

Placebo

0.5%

0.2%

0.8%

0.3%

1.1%

0.3%

0.6%

0.1%

^aThese sexual adverse reactions are associated with dutasteride treatment( including monotherapy and combination with tamsulosin).These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown.

^bIncludes breast tenderness and breast enlargement.

Long-Term Treatment (Up to 4 Years)

High-grade prostate cancer: A randomized, double-blind, placebo-controlled trial enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months to evaluate the role of dutasteride in prevention of prostate cancer. Subjects were randomized to receive placebo (N=4,126) or 0.5 mg daily doses of dutasteride (N=4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had ‘for-cause biopsies’ at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8–10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%). In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg), similar results for Gleason score 8–10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride.

Reproductive and Breast Disorders

In the three pivotal placebo-controlled BPH trials with dutasteride, each of 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these three trials, there was one case of breast cancer in the dutasteride group and one case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial. The relationship between the long-term use of dutasteride and male breast neoplasia is currently unknown.

Combination with Alpha-Blocker Therapy

Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian.

The most common adverse reactions reported in ≥ 1% subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.

Cardiac Failure: In a trial with combination therapy with dutasteride and alpha-blocker, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or in combination with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dutasteride. 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. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to dutasteride.

Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized oedema, serious skin reactions, and angio-oedema.

Neoplasms: Male breast cancer.

Psychiatric Disorders: Depressed mood

Reproductive system and Breast disorders: Testicular pain and testicular swelling.

Reporting of suspected adverse reactions

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla ltd. on 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Silodosin

Silodosin 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 silodosin 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.

Dutasteride

In volunteer studies, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical study, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg.

There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.

Pharmacological Properties

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in the prostate size, caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet.

SILOFAST D 4/8 mg bilayer tablet is a Fixed dose combination tablet of silodosin 4mg/8mg and dutasteride 0.5 mg.

Mechanism of Action

Silodosin

Silodosin is a selective antagonist of post-synaptic alpha₁-adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule and prostatic urethra. Blockade of these alpha₁-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 the binding affinity of silodosin to the three subtypes of the alpha₁-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.

Dutasteride

Dutasteride inhibits the conversion of testosterone to DHT. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme, 5 alpha-reductase, which exists as two isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.

Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

Pharmacodynamic Properties

Silodosin

Orthostatic Effects

A test for postural hypotension was conducted 2 to 6 hours after the first dose in 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 mm Hg decrease in systolic blood pressure, or a >20 mm Hg decrease in diastolic blood pressure, or a >20 bpm increase in heart rate

Table 3: Summary of Orthostatic Test Results in 12-week, Placebo-Controlled Clinical Trials

Time of Measurement

Test Result

Silodosin

N=466

n (%)

Placebo

N=457

n (%)

1 minute after standing

Negative

Positive

459 (98.7)

6 (1.3)

454 (99.6)

2 (0.4)

3 minutes after standing

Negative

Positive

456 (98.1)

9 (1.9)

454 (99.6)

2 (0.4)

Cardiac Electrophysiology

The effect of silodosin 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 silodosin 8 mg, silodosin 24 mg, or placebo once daily for 5 days, or a single dose of moxifloxacin 400 mg on day 5 only. The 24 mg dose of silodosin 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 cytochrome (CY) P3A4 inhibitors)

QT interval was measured during a 24-hour period following dosing on day 5 (at silodosin steady state).

Silodosin 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.

Dutasteride

Effect on 5 Alpha DHT and Testosterone

The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.

In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001).

Adult males with genetically inherited type 2, 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase-deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase deficiency have been observed in these individuals.

Effects on Other Hormones

In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n=26) resulted in no clinically significant change compared with placebo (n=23) in sex hormone-binding globulin, oestradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.

Other Effects

Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e. total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n=13) of the 1-year healthy volunteer trial.

Pharmacokinetic Properties

Silodosin

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 4 presents the steady state pharmacokinetics of this study.

Table 4: Mean (±SD) Steady-State Pharmacokinetic Parameters in Healthy Males Following Silodosin 8 mg Once Daily with Food

C_max (ng/mL)	t_max (hours)	t_1/2 (hours)	AUC_ss (ng•hr/mL)
61.6 ± 27.54	2.6 ± 0.90	13.3 ± 8.07	373.4 ± 164.94

C_max = maximum concentration, t_max = time to reach C_max, t_1/2 = elimination half-life, AUC_ss = steady-state area under the concentration-time curve

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 pharmacokinetics of silodosin was not evaluated. The effect of a moderate-fat, moderate-calorie meal was variable and decreased silodosin C_max by approximately 18 to 43% and exposure AUC by 4 to 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 (CYP450 3A4) pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD-3213G) that is formed via the 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 silodosin.

Excretion

Following oral administration of ¹⁴C-labelled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in the urine and 54.9% in the faeces. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour.

Pharmacokinetics in 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 C_max of silodosin was observed

Paediatric: Silodosin has not been evaluated in patients less than 18 years of age.

Renal Impairment: In a study with 6 subjects with moderate renal impairment, the total silodosin (bound and unbound) AUC, C_max, and elimination half-life were 3.2-, 3.1-, and 2-fold higher, respectively, compared with 7 subjects with normal renal function. The unbound silodosin AUC and C_max were 2.0- and 1.5-fold higher, respectively, in subjects with moderate renal impairment compared with 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 silodosin daily than in subjects with normal or mildly impaired renal function

Hepatic Impairment: In a study comparing 9 male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), with 9 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 has not been studied.

Dutasteride

Absorption

Following administration of a single 0.5 mg dose of dutasteride, time to peak serum concentrations (T_max) occurs within 2 to 3 hours. Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10 to 15%. This reduction is of no clinical significance.

Distribution

Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha₁-acid glycoprotein (96.6%). In a trial of healthy subjects (n=26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months, 11.5% of serum dutasteride concentrations partitioned into semen.

Metabolism

Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by the human CYP450 isoenzymes, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to the steady state, unchanged dutasteride, three major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and two minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6 beta-hydroxydutasteride is comparable to that of dutasteride.

Excretion

Dutasteride and its metabolites were excreted mainly in the faeces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%).

The terminal elimination half-life of dutasteride is approximately 5 weeks at the steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.

Pharmacokinetics in Special Populations

Paediatric: Dutasteride pharmacokinetics has not been investigated in subjects younger than 18 years of age.

Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5 mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the three pivotal trials, 60% were aged 65 years and over, and 15% were aged 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender: Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women. The pharmacokinetics of dutasteride in women has not been studied.

Race: The effect of race on dutasteride pharmacokinetics has not been studied.

Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients.

Non-Clinical Properties

Silodosin

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).

Dutasteride

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.

In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydigcells and an increase in circulating luteinizing hormone levels has been demonstrated with 5 alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5 alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure.

Mutagenesis: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.

Impairment of Fertility

Treatment of sexually mature male rats with dutasteride at 0.1 times the MRHD (animal doses of 0.05 mg/kg/day or greater for up to 31 weeks) based on mean serum concentration resulted in dose-and time-dependent decreases in fertility at all doses; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes (cytoplasmic vacuolation of tubular epithelium in the epididymides and/or decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles) in the reproductive organs at all doses in the absence of paternal toxicity. The fertility effects were reversed by Recovery Week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The microscopic changes were no longer present at Recovery Week 14 at 0.1 times the MRHD and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to treated males (10 to 500 mg/kg/day for 29 to 30 weeks) which are 16 to 110 times the MRHD based on mean serum concentration. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats.

In a fertility study in female rats with dosing 4 weeks prior to mating through early gestation, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size due to increased resorptions and in feminization of male fetuses (decreased anogenital distance) at 2 to 10 times the MRHD (animal doses of 2.5 mg/kg/day or greater) based on mean serum concentration, in the presence of maternal toxicity (decreased body weight gain). Fetal body weights were also reduced at approximately 0.02 times the MRHD (rat dose of

0.05 mg/kg/day or greater) based on mean serum concentration, with no no-effect level, in the absence of maternal toxicity.

Animal Toxicology and/or Pharmacology

Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively.

Rabbit Dermal Absorption

In a rabbit dermal pharmacokinetics study, dermal absorption of dutasteride in CAPMUL (glyceryl oleate) in rabbits resulted in serum concentrations of 2.7 to 40.5 mcg/h/mL for doses of 1 to 20 mg/mL, respectively, or 56% to 100% of applied dutasteride to be absorbed under occluded and prolonged conditions. AVODART soft gelatin capsules administered orally contain 0.5 mg dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. Dutasteride in water was minimally absorbed in rabbits (2,000 mg/kg).

Description

Silodosin

Silodosin is a selective antagonist of post-synaptic alpha₁-adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha₁-adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms.

The chemical name of silodosin is 1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2trifluoroethoxy)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:

Dutasteride

Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type I and type II isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to 5 alpha-dihydrotestosterone (DHT).

Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3 oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C₂₇H₃₀F₆N₂O₂, representing a molecular weight of 528.5 with the following structural formula:

Pharmaceutical Particulars

Shelf-Life

24 months

Packaging Information

SILOFAST D 4: Uncoated bilayer tablet containing Silodosin 4mg and Dutasteride 0.5mg 10 tablets Blister Pack

SILOFAST D 8: Uncoated bilayer tablet containing Silodosin 8mg and Dutasteride 0.5mg 10 tablets Blister Pack.

Storage and Handing Instructions

Store below 30°C. Protect from light & moisture.

Patient Counselling Information

What is SILOFAST D?

SILOFAST D is a prescription medicine that contains silodosin and dutasteride. SILOFAST D is used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

Improve symptoms
Reduce the risk of acute urinary retention (a complete blockage of urine flow)
Reduce the risk of the need for BPH-related surgery

Who should NOT take SILOFAST D?

Do Not Take SILOFAST D if you are:

• pregnant or could become pregnant. SILOFAST D may harm your unborn baby. Pregnant women should not touch SILOFAST D Tablets. If a woman who is pregnant with a male baby gets enough SILOFAST D in her body by swallowing or touching SILOFAST D, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking SILOFAST D Tablets, the contact area should be washed immediately with soap and water.

a child or a teenager.
allergic to dutasteride or any of the ingredients in SILOFAST D. See the end of this leaflet for a complete list of ingredients in SILOFAST D.
allergic to other 5 alpha-reductase inhibitors, for example, finasteride Tablets.

What should I tell my healthcare provider before taking SILOFAST D?

Before you take SILOFAST D, tell your healthcare provider if you:

• have liver problems

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. SILOFAST D and other medicines may affect each other, causing side effects. SILOFAST D may affect the way other medicines work, and other medicines may affect how SILOFAST D works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

Patients should be instructed to take SILOFAST D once daily with a meal. Patients should be instructed about the possible occurrence of symptoms related to postural hypotension (such as dizziness), and should be cautioned about driving, operating machinery, or performing hazardous tasks until they know how SILOFAST D will affect them. This is especially important for those with low blood pressure or who are taking antihypertensive medications.

The patient should be instructed to tell his ophthalmologist about the use of SILOFAST D before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking SILOFAST D.

How should I take SILOFAST D?

Take 1 SILOFAST D tablet once a day.
Swallow SILOFAST D tablets whole. Do not crush, chew, or open SILOFAST D because the contents of the tablet may irritate your lips, mouth, or throat.
You can take SILOFAST D with or without food.
If you miss a dose, you may take it later that day. Do not make up the missed dose by taking 2 doses the next day.

What should I avoid while taking SILOFAST D?

• You should not donate blood while taking SILOFAST D or for 6 months after you have stopped SILOFAST D. This is important to prevent pregnant women from receiving SILOFAST D through blood transfusions.

What are the possible side effects of SILOFAST D?

The most common side effect seen with SILOFAST D is an orgasm with reduced or no semen. This side effect does not pose a safety concern and is reversible with discontinuation of the product.

SILOFAST D may cause serious side effects, including:

• Rare and serious allergic reactions, including:

swelling of your face, tongue, or throat
serious skin reactions, such as skin peeling

Get medical help right away if you have these serious allergic reactions.

• Higher chance of a more serious form of prostate cancer.

The most common side effects of SILOFAST D include:

trouble getting or keeping an erection (impotence)
a decrease in sex drive (libido)
ejaculation problems
enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.

SILOFAST D has been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of SILOFAST D on male fertility is not known.

Prostate Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate problems, including prostate cancer before you start and while you take SILOFAST D. A blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. SILOFAST D will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with SILOFAST D (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects with SILOFAST D. For more information, ask you healthcare provider or pharmacist.

Reporting of suspected adverse reactions

How should I store SILOFAST D?

Store below 30°C. Protect from light & moisture

What are the ingredients in SILOFAST D?

Active ingredient: Silodosin and Dutasteride