Silosure D

Uses

Dutasteride is used for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

• Improve symptoms
• Reduce the risk of acute urinary retention
• Reduce the risk of the need for BPH-related surgery

Silodosin, a selective alpha-1 adrenergic receptor antagonist, is used for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin is not used for the treatment of hypertension.

Silosure D is also used to associated treatment for these conditions: Benign Prostatic Hyperplasia (BPH), Symptomatic Benign Prostatic HyperplasiaBenign Prostatic Hyperplasia (BPH)

How Silosure D works

The 5α-reductase is a nuclear-bound steroid intracellular enzyme primarily located in the prostatic stromal cell that converts the androgen testosterone into the more active metabolite, 5α-dihydrotestosterone (DHT). DHT is considered to be the primary androgen playing a role in the initial development and subsequent enlargement of the prostate gland. It serves as the hormonal mediator for the hyperplasia upon accumulation within the prostate gland. DHT displays a higher affinity towards androgen receptors in the prostate gland compared to testosterone and by acting on the androgen receptors, DHT modulates genes that are responsible for cell proliferation. Responsible for the synthesis of approximately one-third of circulating DHT, type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including the scalp, and liver. The type II 5a-reductase isozyme is primarily found in the prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. Due to its dual inhibition of both isoenzymes of 5α-reductase, dutasteride causes a near-complete suppression of DHT. Compared to a 70% reduction of serum DHT levels caused by finasteride, a near-complete suppression of serum DHT-more than 90% is seen with dutasteride.

By forming a stable complex with both type II and type II 5α-reductase, dutasteride inhibits its enzymatic action of converting testosterone to 5α-dihydrotestosterone (DHT), which is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. It is proposed that DHT is the principal androgen responsible for prostatic growth in later life-normal masculinization of the external genitalia and maturation of the prostate gland during development-thus reducing the serum DHT levels results in reduced prostatic volume and increased epithelial apoptosis. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5α-reductase isoenzymes and when evaluated under in vitro and in vivo conditions, the dissociation of the drug from the drug-enzyme complex is reported to be extremely slow. Dutasteride does not bind to the human androgen receptor.

The pathogenesis of benign prostatic hyperplasia is not fully understood: it is believed to involve several pathways, including inflammation, apoptosis, and cellular proliferation. Most drug therapies aim to alleviate symptoms of benign prostatic hyperplasia, silodosin included. Lower urinary tract symptoms of benign prostatic hyperplasia are categorized into three main groups: voiding or obstructive (hesitancy, slow stream, intermittency, incomplete emptying), storage or irritative (frequency, urgency, nocturia, urge urinary incontinence), and postmicturition (postvoid dribbling). Prostate contraction is the main contributor to lower urinary tract symptoms of benign prostatic hyperplasia. The smooth muscle tone of the prostate is regulated by α_1A-adrenoceptors, which are the most highly expressed subtype of α₁adrenoceptors in the human prostate tissue. It has been reported that blockade of α_1A-adrenoceptors relieves bladder outlet obstruction. Blockade of α_1D-adrenoceptors, another subtype found in prostate tissue, is believed to alleviate storage symptoms due to detrusor overactivity.

α₁-adrenoceptors are G protein-coupled receptors: upon binding of its natural ligand, norepinephrine and epinephrine, leads to the activation of phospholipase C and downstream signalling molecules, including inositol triphosphate and diacylglycerol. Ultimately, there is an increase in intracellular calcium levels and, consequently, smooth muscle contraction. Silodosin is an antagonist of α₁-adrenoceptors, with the highest selectivity for the α_1A-adrenoceptor subtype. By blocking the α_1A-adrenoceptor signalling pathway, silodosin promotes prostatic and urethral smooth muscle relaxation, thereby improving lower urinary tract symptoms such as voiding. Silodosin also targets afferent nerves in the bladder, relieving bladder overactivity and storage symptoms.

Dosage

Silosure D dosage

The recommended dose is Dutasteride 0.5 mgorally once daily. The capsules should be swallowed whole. Dutasteride may be administered with or without food.

The recommended dose is Silodosin 8 mg orally once daily with a meal.4 mg capsules taken orally once daily with a meal for those with moderate renal impairment (CrCl 30-50 mL/min).

Side Effects

• Sexual problems (such as decreased sexual interest/ ability, decrease in the amount of semen/ sperm released during sex)
• Impotence (trouble getting or keeping an erection)
• Testicle pain or swelling
• Increased breast size
• Breast tenderness.

Most common adverse reactions are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis and nasal congestion.

Toxicity

LD50 values

The estimated dermal LD50 of dutasteride in rabbits is > 2,000 mg/kg.

Overdose

In studies of volunteers receiving single doses of dutasteride up to 40 mg (which is 80 times the therapeutic dose) for 7 days, there were no reports of clinically significant adverse events. Low incidences of impotence, reduced libido, gynecomastia, and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients. There are no known antidotes for dutasteride. In case of overdose, appropriate symptomatic and supportive treatment should be given.

Nonclinical Toxicology

In a 2-year carcinogenicity mouse study, there was an increased incidence of benign hepatocellular adenomas in female mice receiving 250 mg/kg/day. An increased incidence of Leydig cell hyperplasia was observed in male rats receiving doses of 7.5 mg/kg/day and greater. At tumorogenic doses, the luteinizing hormone (LH) levels in rats were increased by 167%. There was no demonstrated a genotoxic potential of dutasteride or its metabolites in a bacterial mutagenesis assay, a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. At much higher doses than the maximum recommended human dose (MRHD) in sexually mature male rats, dutasteride caused a dose- and time-dependent decrease in fertility, 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 in the male reproductive organs. At exposures 425- and 315-fold the expected clinical exposure of dutasteride in rats and dogs, respectively, there were some signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes.

Pregnancy and Lactation

As DHT is a necessary hormone for the development of male genitalia, exposure to dutasteride in pregnant women bearing male fetuses may cause fetal harm. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Although it is not known whether dutasteride is excreted in human milk, the use of dutasteride in women of childbearing potential, including nursing women. In elderly patients, the half-life of dutasteride may increase. As the renal elimination of dutasteride is very minimal, the use of dutasteride in patients renal insufficiency is reported to be safe. There are no specific dosage adjustment recommendations for use in elderly patients or patients with renal impairment.

Oral LD₅₀ is 800 mg/kg in rats.

In clinical trials, postural hypotension was the most common dose-limiting adverse event. In case of drug overdose leading to hypotension, the patient should be placed in a supine position to restore blood pressure and normalize heart rate. Further measures, such as administration of intravenous fluids, may be initiated. In case of the use of vasopressors, renal function should be monitored and supported as needed. Since silodosin is highly bound to plasma proteins, dialysis is unlikely to be beneficial.

Precaution

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with Dutasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5 a-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy. 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.

Postural hypotension with or without symptoms (e.g. dizziness) may develop when beginning Silodosin treatment. Silodosin should not be used in combination with other alpha-blocker. Inform patients planning cataract surgery to notify their ophthalmologist that they are taking Silodosin because of the possibility of Intraoperative Floppy Iris Syndrome (IFIS)

Interaction

Care should be taken when administering Dutasteride to patients taking potent, chronic CYP3A4 inhibitors. Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 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. In vitro studies demonstrate that Dutasteride does not displace Warfarin, Diazepam, or Phenytoin from plasma protein binding sites, nor do these model compounds displace Dutasteride.

Strong P-glycoprotein inhibitors (e.g., cyclosporine): Co-administration may increase plasma Silodosin concentration. Concomitant use of PDE5 inhibitors with alpha-blockers including Silodosin can potentially cause symptomatic hypotension.

Volume of Distribution

Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen.

Silodosin has an apparent volume of distribution of 49.5 L.

Elimination Route

Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug.

The absolute bioavailability is approximately 32%. Following oral administration of silodosin 8 mg once daily in healthy male subjects, C_max was 61.6 ± 27.54 ng/mL and AUC was 373.4 ± 164.94 ng x hr/mL. The T_max was 2.6 ± 0.90 hours. Silodosin glucuronide or KMD-3213G, the main metabolite of silodosin, has an AUC three- or four fold higher than for the parent compound.

A moderate fat or calorie meal reduces C_max by 18% to 43% and AUC by 4% to 49%, as well as T_max by about one hour. However, the US prescribing information recommends drug intake with meals to avoid the potential adverse effects associated with high plasma drug concentrations.

Half Life

The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. This long half-life accounts for the serum concentrations remaining detectable for up to 4 to 6 months after discontinuation of treatment.

The elimination half-life of silodosin is 13.3 ± 8.07 hours. KMD-3213G, the main metabolite of silodosin, has an extended half-life of approximately 24 hours.

Clearance

In a study of healthy volunteers receiving single oral doses of dutasteride ranging from 0.01 to 40 mg, dutasteride displayed a low linear clearance of 0.58 L/h. The estimated inter-individual variability for the linear clearance was high.

After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour.

Elimination Route

Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%.

At 10 days following oral administration of radiolabelled silodosin, about 33.5% of the dose was recovered in urine and 54.9% was recovered in feces.

Pregnancy & Breastfeeding use

Pregnancy Category X. Dutasteride is contraindicated for use in women.

Pregnancy Category B. Silodosin is not indicated for use in women. An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/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 1000 mg/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 300 mg/kg/day.

Contraindication

Dutasteride is contra-indicated for use in women and children and for patients with known hypersensitivity to Dutasteride, and other 5 a-reductase inhibitors. Warnings: Exposure of women-risk to male fetus: Dutasteride is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle Dutasteride capsules because of the possibility of absorption of Dutasteride and the potential risk of a fetal anomaly to a male fetus. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Patients with severe renal & hepatic impairment, concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) and patients with a history of hypersensitivity to Silodosin.

Special Warning

Pediatric use: Dutasteride is not indicated for use in the pediatric population. Safety and effectiveness in the pediatric population have not been established.

Geriatric use: No overall differences in safety or efficacy were observed between elderly and adult subjects.

Elderly use: No dosage adjustment is necessary for subjects with renal impairment or for the elderly.

Hepatic impairment: Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made.

Pediatric patients: Silodosin is not indicated for use in pediatric patients.

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: Silodosin is contra-indicated in patients with severe renal impairment (CCr <30 mL/min). In patients with moderate renal impairment (CCr 30-50 mL/min), the dose should be reduced to Silodosin 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80 mL/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.

Acute Overdose

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.

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.

Storage Condition

Store in a cool and dry place, protected from light

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

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