Maxvoid S

Uses

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.

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome.

Maxvoid S is also used to associated treatment for these conditions: Benign Prostatic Hyperplasia (BPH)Benign Prostatic Hyperplasia (BPH), Urinary Bladder, Overactive

How Maxvoid S works

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.

Solifenacin is a competitive muscarinic receptor antagonist. It has the highest affinity for M3, M1, and M2 muscarinic receptors. 80% of the muscarinic receptors in the bladder are M2, while 20% are M3. Solifenacin's antagonism of the M3 receptor prevents contraction of the detrusor muscle, while antagonism of the M2 receptor may prevent contraction of smooth muscle in the bladder.

Dosage

Maxvoid S dosage

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).

Adults, including the elderly: The recommended dose is Solifenacin Succinate 5 mg once daily. If needed, the dose may be increased to Solifenacin Succinate 10 mg once daily.

Children and adolescents: Safety and effectiveness in children have not yet been established. Therefore, Solifenacin Succinate should not be used in children.

Side Effects

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

The most common side effects are blurred vision, dry mouth, constipation & heat prostration. Other side effects include dizziness, fatigue, edema, palpitation and skin reactions. Disorientation, hallucination and convulsion may occur.

Toxicity

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.

The LD₅₀ of Solifenacin has yet to be determined.

Signs of overdose include severe anticholinergic effects, mental status changes, and decreased consciousness. In case of overdose, treat patients with gastric lavage and supportive measures. Monitor patients with an ECG.

Precaution

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)

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Solifenacin. If urinary tract infection is present, an appropriate antibacterial therapy should be started. Solifenacin Succinate should be used with caution in patients with clinically significant bladder outflow obstruction at risk of urinary retention, gastrointestinal obstructive disorders, risk of decreased gastrointestinal motility, severe renal impairment (creatinine clearance 30 ml/min), moderate hepatic impairment, concomitant use of a strong CYP3A4 inhibitor, e.g. ketoconazole

Interaction

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.

Concomitant medication with other drugs with anticholinergic properties may result in more pronounced therapeutic effects and side effects. The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists. Solifenacin can reduce the effect of drugs that stimulate the motility of the gastro-intestinal tract, such as metoclopramide and cisapride. Ketoconazole & other CYP3A4 inhibitors increase the plasma concentration of solifenacin.

Volume of Distribution

Silodosin has an apparent volume of distribution of 49.5 L.

The volume of distribution of solifenacin is 600L.

Elimination Route

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.

Solifenacin is well absorbed in the duodenum, jejunum, and ileum but not the stomach. Absorption occurs via passive diffusion and so no transporters are involved. The mean oral bioavailability of solifenacin is 88%. The T_max of solifenacin is 3-8 hours with a C_ss of 32.3ng/mL for a 5mg oral dose and 62.9ng/mL for a 10mg oral dose.

Half Life

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.

The elimination half life of solifenacin ranges from 33-85 hours.

Clearance

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

The clearance of solifenacin is 7-14L/h and a renal clearance of 0.67-1.51L/h.

Elimination Route

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.

69.2±7.8% of a radiolabelled dose is recovered in the urine, 22.5±3.3% was recovered in feces, and 0.4±7.8% was recovered in exhaled air. 18% of solifenacin is eliminated as the N-oxide metabolite, 9% is eliminated as the 4R-hydroxy N-oxide metabolite, and 8% is eliminated as the 4R-hydroxy metabolite.

Pregnancy & Breastfeeding use

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.

Use in pregnancy: There are no adequate data from the use of solifenacin succinate in pregnant women. Caution should be exercised while prescribing solifenacin to pregnant women.

Use in lactating mother: No data concerning the excretion of solifenacin into breast milk are available. The use of Solifenacin is avoided in lactating mother.

Contraindication

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.

Solifenacin is contraindicated in patients with hypersensitivity to solifenacin or to any of the excipients. It is also contraindicated in myasthenia gravis, urinary retention, uncontrolled narrow angle glaucoma, severe gastro-intestinal condition (including toxic megacolon), patients undergoing haemodialysis, patients with severe hepatic impairment, patients with severe renal impairment or moderate hepatic impairment and on treatment with a strong CYP3A4 inhibitor, e.g. ketoconazole.

Special Warning

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.

Patients with renal impairment: No dosage adjustment is necessary for patients with mild to moderate renal impairment (creatinine clearance > 30 ml/min). Patients with severe renal impairment (creatinine clearance 30 ml/min) should be treated with caution and receive no more than 5 mg Solifenacin SuccinateTablet once daily.

Patients with hepatic impairment: No dosage adjustment is necessary for patients with mild hepatic impairment. Patients with moderate hepatic impairment should be treated with caution and receive no more than 5 mg Solifenacin SuccinateTablet once daily.

Patients taking CYP3A4 inhibitors concomitantly: The maximum dose of Solifenacin Succinateshould be limited to 5 mg when treated simultaneously with ketoconazole or other potent CYP3A4 inhibitors e.g. ritonavir, nelfinavir or itraconazole.

Use in children: Safety and efficacy of solifenacin in children have not been established.

Acute Overdose

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.

Innovators Monograph

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