Rapasin Capsule 8mg

Product Information

RAPASIN

Rapasin®

Silodosin

Presentation

Rapasin 4 capsule: Opaque white cap imprinted with ‘RSN’ and opaque white body imprinted with ‘4mg’ capsule; each capsule contains

Silodosin INN 4mg.

Rapasin 8 capsule: Opaque white cap imprinted with ‘RSN’ and opaque white body imprinted with ‘8mg’ capsule; each capsule contains

Silodosin INN 8mg .

Indications

Rapasin (Silodosin), a selective alpha-1 adrenergic receptor antagonist, is indicated for the treatment of the signs and symptoms

of benign prostatic hyperplasia (BPH). Rapasin (Silodosin) is not indicated for the treatment of hypertension.

Dosage and administration

The recommended dose is Silodosin 8mg (one Rapasin 8 capsule) orally once daily with a meal.

Dosage adjustment in special populations

Renal impairment: Silodosin is contra-indicated in patients with severe renal impairment (CCr < 30mL/min). In patients with

moderate renal impairment (CCr 30-50mL/min), the dose should be reduced to Silodosin 4mg (one Rapasin 4 capsule) once daily taken

with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80mL/min).

Hepatic impairment: Silodosin has not been studied in patients with severe hepatic impairment (Child-Pugh score > 10) and is

therefore contra-indicated in these patients. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

Contra-indications, warnings etc.

Contra-indications: Silodosin capsules are contra-indicated in patients with severe renal impairment (CCr < 30mL/min), severe

hepatic impairment (Child-Pugh score > 10), concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g.,

Ketoconazole, Clarithromycin, Itraconazole, Ritonavir) and in patients with a history of hypersensitivity to Silodosin.

Warnings and precautions: 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.

Renal impairment: In a clinical pharmacology study, plasma concentrations (AUC and Cmax) of Silodosin were approximately three

times higher in subjects with moderate renal impairment compared with subjects with normal renal function, while half-lives of

Silodosin doubled in duration. The dose of Silodosin should be reduced to 4mg in patients with moderate renal impairment. Exercise

caution and monitor such patients for adverse events.

Hepatic impairment: Silodosin has not been tested in patients with severe hepatic impairment, and therefore, should not be

prescribed to such patients.

Pharmacokinetic drug-drug interactions: In a drug interaction study, co-administration of a single 8mg dose of Silodosin with

400mg 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 contra-indicated.

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 co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators

that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. 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.

Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some

patients on alpha-1 blockers or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by

the combination of a flaccid iris that billows in response to intraoperative irrigation currents; progressive intraoperative

miosis despite preoperative dilation with standard mydriatic drugs; and potential prolapse of the iris toward the

phacoemulsification incisions. Patients planning cataract surgery should be told to inform their ophthalmologist that they are

taking 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 prostate-specific antigen (PSA).

Use in pregnancy: Pregnancy Category B. Silodosin is not indicated for use in women. An embryo/fetal study in rabbits showed

decreased maternal body weight at 200mg/kg/day (approximately 13-25 times the maximum recommended human exposure or MRHE of

Silodosin via AUC). No statistically significant teratogenicity was observed at this dose. Silodosin was not teratogenic when

administered to pregnant rats during organogenesis at 1000mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal

or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated Silodosin, which is present in human

serum at approximately 4 times the level of circulating Silodosin and which has similar pharmacological activity to Silodosin. No

effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at

up to 300mg/kg/day.

Pediatric use: Silodosin is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not

been established.

Geriatric use: In double-blind, placebo-controlled, 12-week clinical studies of Silodosin, 259 (55.6%) were under 65 years of age,

207 (44.4%) patients were 65 years of age and over, while 60 (12.9%) patients were 75 years of age and over. Orthostatic

hypotension was reported in 2.3% of Silodosin patients < 65 years of age (1.2% for placebo), 2.9% of Silodosin patients > 65 years

of age (1.9% for placebo), and 5.0% of patients > 75 years of age (0% for placebo). There were otherwise no significant

differences in safety or effectiveness between older and younger patients.

Renal impairment: The effect of renal impairment on Silodosin pharmacokinetics was evaluated in a single dose study of six male

patients with moderate renal impairment and seven male subjects with normal renal function. Plasma concentrations of Silodosin

were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal

function. Silodosin should be reduced to 4mg per day in patients with moderate renal impairment. Exercise caution and monitor

patients for adverse events. Silodosin has not been studied in patients with severe renal impairment. Silodosin is

contra-indicated in patients with severe renal impairment.

Hepatic impairment: In a study comparing nine male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), to nine

healthy male subjects, the single dose pharmacokinetics of Silodosin were not significantly altered in patients with hepatic

impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment.

Drug interactions: Moderate and 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 concentration of Silodosin. Exercise caution and monitor patients for adverse events when co-administering

Silodosin with moderate CYP3A4 inhibitors. 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 therefore 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. PDE5 inhibitors: Co-administration of

Silodosin with a single dose of 100mg Sildenafil or 20mg 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). Exercise caution during concomitant use with antihypertensives and monitor

patients 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.

Food interactions: The effect of a moderate fat, moderate calorie meal on Silodosin pharmacokinetics was variable and decreased

Silodosin maximum plasma concentration (Cmax) by approximately 18-43% and exposure (AUC) by 4-49% across three different studies.

Safety and efficacy clinical trials for 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.

Side effect: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and

may not reflect the rates observed in clinical practice. In U.S. clinical trials, 897 patients with BPH were exposed to 8mg

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, multicenter, double-blind, placebo-controlled clinical studies of Silodosin 8mg 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

Table1.

In the two 12-week, placebo-controlled clinical trials, the following adverse events were 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 rhinorrhea. 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

(IFIS) 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 edema

resulting in serious outcomes

Overdose: Silodosin was evaluated at doses of up to 48mg/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.

Pharmaceutical precautions

Store in a cool and dry place, protected from light.

Packaging quantities

Rapasin 4 capsule: Carton containing 16 capsules in alu-alu blisters.

Rapasin 8 capsule: Carton containing 16 capsules in alu-alu blisters.

Manufactured by

UniMed & UniHealth Manufacturers Ltd.

Gazipur, Bangladesh

® Registered Trademark