, Volume 19, Issue 2, pp 135-161
Date: 31 Aug 2012

Tamsulosin

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Summary

Abstract

Tamsulosin is a subtype-selective α1A- and α1D-adrenoceptor antagonist. α1-Receptors predominate in the prostate gland, prostatic capsule, prostatic urethra and bladder, and the relaxation of prostate and bladder smooth muscles is associated with improved maximal urine flow (Qmax) and alleviation of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH).

Tamsulosin 0.4mg once daily in a modified-release formulation increased Qmax and improved symptom scores relative to baseline to a greater extent than placebo in 12- and 13-week double-blind, randomised, multicentre, clinical trials in patients with LUTS, with statistical significance between treatments for Qmax values in two of three published US and European studies. Tamsulosin is effective in patients with mild to severe LUTS associated with BPH, in patients with diabetes mellitus and in the elderly, and does not interfere with concomitant antihypertensive therapy. Pooled data based on patients receiving tamsulosin 0.4 or 0.8mg once daily indicate maintenance of efficacy for up to 6 years.

Tamsulosin 0.4mg once daily was of similar efficacy to alfuzosin 2.5mg three times daily, with less tendency to cause hypotensive effects, in a double-blind, randomised 12-week trial. Benefit of the drug has also been shown in patients with acute urinary retention or chronic abacterial prostatitis, those receiving high energy transurethral microwave thermotherapy, and in patients with prostate cancer with radiation-induced urethritis.

Dizziness and abnormal ejaculation are stated to be the most common adverse events, with asthenia, postural hypotension and palpitations being seen less frequently (1 to 2% incidence), in patients receiving tamsulosin 0.4mg once daily. Tamsulosin has not been associated with clinically significant changes in blood pressure in clinical trials.

Conclusion: The α1A- and α1D-adrenoceptor antagonist tamsulosin, given at a dosage of 0.4mg once daily in a modified-release formulation, is effective and well tolerated in the treatment of LUTS associated with BPH. Although the drug has been directly compared to date with one other agent only, data show overall that tamsulosin clearly offers advantages over other α1-adrenoceptor antagonists in terms of the need for a single daily dose only, and its low potential for hypotensive effects or interference with concomitant antihypertensive therapy. Dosage titration at the start of treatment is not necessary. Tamsulosin has a rapid onset of action and is effective in patients with moderate or severe symptoms. The drug is therefore a valuable therapeutic option, with both demonstrated and potential advantages over older nonselective agents, in the management of patients with LUTS associated with BPH.

Pharmacodynamic Properties

Tamsulosin is a subtype-selective α1-adrenoceptor antagonist with a greater selectivity for prostatic tissues (where α1A-adrenoceptors predominate) than for vascular tissues (α1B-predominant). In contrast, other α1-adrenoceptor antagonists (e.g. prazosin, terazosin, doxazosin and alfuzosin) show minimal subtype selectivity.

The efficacy of tamsulosin is attributable to the blockade of α1A-adrenoceptors in the prostate gland. This inhibits smooth muscle contraction and improves dynamic voiding, which leads in turn to an improvement in the maximum urinary flow rate (Qmax). The blockade of α1A- and α1D-adrenoceptors in the bladder results in the inhibition of detrusor muscle contractions, which leads to reduced detrusor muscle instability and reduction of storage symptoms.

Tamsulosin is associated with a low potential for vasodilation and associated cardiovascular adverse effects. The vascular α1-adrenoceptor activity of single doses of tamsulosin 0.2mg, assessed by finger skin vasoconstrictor response to cold stimulation and dorsal vein constrictor response to increasing doses of phenylephrine, was similar to that of placebo and less than that of doxazosin 1mg, terazosin 1mg or tamsulosin 0.6mg in studies in healthy volunteers.

Tamsulosin 0.4 mg/day does not appear to have any clinically significant effect on prostate specific antigen levels.

Pharmacokinetic Properties

Tamsulosin displays linear kinetics after administration of single and multiple doses. Plasma concentrations are associated with considerable interindividual variability, and steady-state plasma concentrations are generally reached within 4 to 7 days. In healthy volunteers aged 55 to 75 years, areas under plasma drug concentration versus time curves (AUCs) were 40% higher than in volunteers aged 20 to 32 years.

Metabolism of tamsulosin takes place in the liver via the cytochrome P450 (CYP) enzyme system (primarily CYP3A4 and CYP2D6), and most of the drug in plasma is unchanged. Unchanged drug accounted for 81% of radioactivity in plasma 0.5 to 4 hours after oral administration of an aqueous solution of radiolabelled tamsulosin 0.2mg; 62% of the drug was recovered in the urine, and unchanged tamsulosin accounted for 8.7% of the dose.

There are no clinically significant differences in the pharmacokinetics of tamsulosin between patients with normal renal function and those with moderate to severe renal impairment. Data indicate that unbound active plasma concentrations of tamsulosin are increased by a factor of 1.5, with increases in renal clearance and percentage excretion of tamsulosin, in patients with moderate hepatic dysfunction relative to healthy individuals. There are no pharmacokinetic data on tamsulosin in patients with severe hepatic impairment.

Therapeutic Efficacy

Once-daily administration of oral tamsulosin 0.4mg as the commercially available modified-release formulation increased Qmax and improved symptom scores to a greater extent than placebo in 12- and 13-week randomised, double-blind, multicentre studies in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Mean increases in Qmax from baseline were greater with tamsulosin (1.4 to 1.75 ml/sec) than with placebo (0.4 to 0.93 ml/sec), with statistical significance (p < 0.05) between treatment arms being attained in two of three published European and US studies. In two of the three studies, significantly more patients were considered responders (≥30% increase in Qmax) in the tamsulosin 0.4mg once daily groups than in the placebo groups. The decrease (improvement) in total Boyarsky symptom score was significantly greater in all tamsulosin-treated groups (3.0 to 4.8 points) than in placebo recipients (1.9 to 3.2 points; p ≤ 0.002). 55 to 70% of tamsulosin recipients responded with ≥25% improvement in Boyarsky symptom score or International Prostate Symptom Score (IPSS), with these proportions of patients being significantly greater than the 40 to 51% of placebo recipients. Subset analysis has indicated improvements in IPSS with tamsulosin to be at least as great in patients with severe LUTS as in those with moderate symptoms. Tamsulosin 0.4mg once daily had a rapid onset of action in these studies, with a significant (p < 0.001 vs placebo) improvement in mean Qmax from baseline being measurable after the first dose of active treatment in one US study.

Meta-analysis of two randomised, double-blind, placebo-controlled European studies (one of which is published) has shown results similar to those reported for individual US and European trials.

Tamsulosin 0.4mg once daily demonstrated similar improvements in Qmax and total Boyarsky symptom score to those seen with alfuzosin 2.5mg three times daily in the treatment of 245 evaluable patients with LUTS in a double-blind, randomised 12-week study; 35 and 34% of patients in the respective treatment groups achieved increases of at least 30% relative to baseline in Qmax.

Improvements in efficacy parameters with tamsulosin 0.4mg once daily were maintained in long-term studies for up to 4 years, and preliminary pooled data from patients receiving either 0.4 or 0.8mg once daily indicate maintenance of efficacy for up to 6 years.

Tamsulosin was as effective in the treatment of LUTS associated with BPH in patients with diabetes mellitus and in the elderly as in patients without diabetes and in younger individuals in retrospective analyses of data from US placebo-controlled trials and in large observational studies. Six-month noncomparative Spanish data obtained in 2740 patients treated with tamsulosin 0.4mg once daily show reductions in IPSS from baseline of 50 to 56% in both the presence and absence of cardiovascular, neurological, psychiatric or diabetic comorbidities (no statistical analysis available).

Preliminary results suggest that the symptoms of radiation therapy-induced urethritis in patients treated for prostate cancer are improved by tamsulosin treatment. In addition, limited data are available to indicate benefit of tamsulosin in patients with acute urinary retention or chronic abacterial prostatitis, and in patients receiving high energy transurethral microwave thermotherapy.

Tolerability

European prescribing information states that dizziness and abnormal ejaculation have been reported most commonly, with headache, asthenia, postural hypotension and palpitations being seen less frequently (1 to 2% incidence) in patients receiving tamsulosin 0.4mg once daily. US prescribing data indicate that headache, dizziness, rhinitis, infection and abnormal ejaculation are the most common adverse events that are probably related to treatment with tamsulosin 0.4mg once daily. With the exception of dizziness, rhinitis and abnormal ejaculation, adverse events show similar incidences to those with placebo. Similar rates of treatment withdrawal were noted for tamsulosin 0.4mg once daily and placebo groups (8 vs 8.5%) in US studies.

Prescription event monitoring involving 7739 patients being prescribed tamsulosin for at least 6 months showed the most frequently reported adverse events to include dizziness, malaise/lassitude, headache/migraine, impotence/ejaculation failure and hypotension.

Long-term therapy with tamsulosin 0.4mg once daily appears on the basis of 4-year data to be well tolerated; the drug has also shown good tolerability in patients with cardiovascular disease or diabetes mellitus, and in patients receiving concomitant antihypertensive agents such as diuretics, β-blockers, calcium channel antagonists or ACE inhibitors.

According to retrospective clinical trial analysis, incidences of abnormal ejaculation with tamsulosin 0.4mg once daily and placebo were 4.5 and 1%, respectively, although there was no increase in sexual dysfunction in patients receiving tamsulosin. There were no statistically significant differences in the incidences of abnormal ejaculation, decreased libido or impotence, or in change in sexual function score, between patients receiving tamsulosin 0.4mg once daily and those receiving alfuzosin 2.5mg three times daily. Relative to placebo, there was a significant improvement (i.e. decrease) in mean total sexual function score in tamsulosin recipients (+0.49 vs −0.31; p = 0.042), although the baseline score was higher (i.e. worse) in the tamsulosin group than in the placebo group (3.35 vs 2.28). Withdrawal rates associated with sexual dysfunction were low with both placebo (0.5%) and tamsulosin (0.8%).

Tamsulosin is associated with a low risk of orthostatic hypotensive effects in patients with LUTS associated with BPH. In clinical trials, tamsulosin 0.4mg once daily showed no clinically relevant hypotensive effect, whereas alfuzosin 2.5mg three times daily was associated with clinically significant reductions in standing and supine diastolic blood pressure (DBP) in a 12-week double-blind comparison of the two drugs. Furthermore, alfuzosin had significantly greater effects on supine and standing systolic blood pressure (SBP) and DBP in patients aged 65 years and over. There were no significant differences between the two treatments with regard to reductions in SBP and DBP in patients with hypertension.

Dosage and Administration

Tamsulosin is indicated for the treatment of the functional symptoms of BPH. The recommended dosage in Europe is 0.4mg once daily after breakfast.

Dosage adjustments are not required on the basis of age or mild to moderate hepatic impairment/renal dysfunction, but hypotensive adverse effects are likely if tamsulosin is given with other α1-adrenoceptor antagonists. Dosage adjustments are also not necessary in patients receiving theophylline, furosemide, cimetidine, atenolol, enalapril or nifedipine. The presence of diclofenac or warfarin may increase the rate of elimination of tamsulosin, however.