COMPOSITION
Silorun-D 4
Each hard gelatin capsule contains:
Silodosin 4mg
Silorun-D 8
Each hard gelatin capsule contains:
Silodosin 8mg
CLINICAL PHARMACOLOGY
Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are found in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. As a result of blockage of these alpha-1 adrenoreceptors, smooth muscle in these tissues relaxes, resulting in an improvement in urine flow and reduction in benign prostatic hyperplasia symptoms. An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 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.
PHARMACOKINETICS
The absolute bioavailability of silodosin is approximately 32%. 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 Cmax by approximately 18-43% and AUC by 4-49% across three different studies. Silodosin is approximately 97% protein bound.
Silodosin undergoes extensive metabolism through glucuronidation, alcohal and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of silodosin as a glucuronide conjugate (KMD-3213G), which has been show in vitro to be active. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and is not expected to contribute significantly to the overall pharmacologic activityo of silodosin.
Following oral administration, silodosin is excreted approximately 33.5% in urine and 54.6% in feces. mean half-life was 13.3+/-8.07 hours. Glucuronide conjugate (KMD-3213G) has an extended half-life of approximately 24 hours. The elimination half-life was approximately 20% greater in the geriatric males compared with the younger males. in patients with moderate renal impairment, the total silodosin (bound and unbound) elimination half-life was approximately 2-fold higher than patients with normal renal function.
INDICATIONS
Silodosin in indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. It is not indicated for the treatment of hypertension.
CONTRAINDICATIONS
> 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)
WARNINGS AND PRECAUTIONS
Orthostatic effects- Postural hypotension, with or without sympotms (e.e., 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 theraphy.
Renal impairment- The effect of renal inpairment 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. Exercise caution and monitor patients for adverse events. Silodosin is contraindicated in patients with severe renal impairment.
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.
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 sholud 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.
Effect on ability to drive and use machines- 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 sholud be cautioned about driving, operating machinery, or performing hazardous tasks when initiating therapy.
Usage in pregnancy and lactation
Silodosin is not indicated for use in women. Silodosin was not teratogenic when administered to experimental animals. No effects on physical or behavioral development of offspring were observed when experimental animals were treated during pregnancy and lactation.
Usage in paediatrics
Silodosin is not indicated for use in paediatric patients. Safety and effectiveness in paediatric patients have not been established.
Orthostatic hypotension was reported in 2.3% of patients <65 years of age (1.2% for placebo), 2.9% 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.
Drug interactions
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.
The effect of moderate VYP3A4 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, 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- 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 does of 100 mg sildenafil or 20 mg tadalafil was evaluated
in a placebo-controlled cilnical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital
signs were monitored in the 12-hours 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 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.
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-epecific antigen (PSA).
ADVERSE DRUG REACTIONS
Adverse reactions observed in at least 2% of patients.
Gastrointestinal disorders-Diarrhoea.
Nervous system disorders-Dizziness headache.
Reproducutive system and breast disorders- Retrograde ejaculation.
Respiratory, thoracic and mediastinal disorders-Nasopharyngitis, nasal congestion
vascular disorders- Orthostatic hypotension
Adverse events reported between 1% and 2% of patients:
Gastrointestinal disorders- Abdominal pain
General disorders and administration site conditions-Asthenia Investigation-PSA increased
Nervous system disorders-Insomnia
Respiratory, thoracic and mediastinal disorders - Sinusitis, rhinorrhea
Following adverse events were reported in single cases:
Eye disorders- intraoperative floppy iris syndrome (IFIS)
Reproductive system and breast disorders-Priapism
Vascular disorders- Syncope (patient taking prazosin concomitantly)
Postmarketing experience
The following adverse reactions have been identified during post approval use of silodosin. Because thses 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
Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values
OVERDOSAGE
Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was
postural hypotension.
Overdose of silodosin lead to hypotension 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 colud 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.
DOSAGE AND ADMINISTRATION
Benign prostate hyperplasis: The recommended dose for the treatment of signs and symptoms of benign prostatic
hyperplasia (BPH) is 8 milligrams orally once daily with a meal.
Dosage in renal impairment: Silodosin is contraindicated in patients with severe renal impairment (CCr<30
mL/min). The dose should be reduced to 4 milligrams once daily taken with meal in patients with moderate renal
impairment (CCr 30 to 50 mL/min). No dosage adjustment is required in patients with mild renal impairment (CCr 50 to 80
mL/min).
Dosage in hepatic impairment: Silodosin is contraindicated in patients with severe hepatic impairment (Child-Pugh score>10). No dosage adjustment is required in patients with mild or moderate hepatic impairment.
Prostate/BPH Related Link
▶ Silorun-D
▶ Dutarun
▶ Tamrun
▶ Tamrun-D