(British Approved Name Modified, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe and Japan.

European Pharmacopoeia, 6th ed. (Tamsulosin Hydrochloride). A white or almost white powder. Slightly soluble in water and anhydrous alcohol freely soluble in formic acid.

Adverse Effects, Treatment, and Precautions

As for Prazosin Hydrochloride. Because tamsulosin is selective for a₁ receptors in the prostate the vasodilator effects may be less frequent. Tamsulosin may cause ejaculation abnormalities. It should be avoided in severe hepatic impairment.

Incidence of adverse effects. A study using prescription event monitoring data for more than 12 000 patients treated with tamsulosin found that dizziness, headache, malaise, and hypotension were the adverse effects most commonly reported.

Surgical procedures. In 2005 the manufacturers of tamsulosin warned that a syndrome of flaccidity of the iris, progressive miosis, and potential prolapse (intraoperative floppy iris syndrome IFIS) had been reported in some patients undergoing cataract surgery who were receiving, or had received, alpha Mockers. One group of workers had reported that in one series of 741 patients undergoing cataract surgery, 15 of the 16 who developed IFIS had received tamsulosin. An earlier retrospective study of 511 similar patients by the same workers had found IFIS in 10 of the 16 patients with a history of tamsulosin treatment but no cases in any of the other patients, including in 11 patients who had received other alpha blockers. The US manufacturer stated that although most cases had occurred in patients who had been taking alpha blockers concurrently or up to 2 weeks before surgery the benefit of stopping such therapy before cataract surgery has not been established as a few cases had included patients who discontinued alpha blockers up to 9 months before surgery. The manufacturers of tamsulosin recommend that patients being considered for cataract surgery should be questioned to ascertain whether they are taking the drug. A literature review found that other alpha blockers, including alfuzosin, doxazosin, and terazosin, have also been associated with IFIS in this patient group however, IFIS has been most strongly associated with the use of tamsulosin. In the UK, the MHRA has required the inclusion of a warning in the labelling of all alpha blockers advising patients to inform their cataract surgeon about past and current use of these drugs.

Interactions

As for Prazosin Hydrochloride.

Pharmacokinetics

Tamsulosin is absorbed from the gastrointestinal tract and is almost completely bioavailable. The extent and rate of absorption are reduced by food. After oral doses of an immediate-release preparation, peak plasma concentrations occur after about 1 hour. Tamsulosin is about 99% bound to plasma proteins. It is metabolised slowly in the liver primarily by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4 it is excreted mainly in the urine as metabolites and some unchanged drug. The plasma elimination half-life has been reported to be between 4 and 5.5 hours. Some of the pharmacokinetic values cited above may be altered when tamsulosin is given as a modified-release preparation, the form in which it is usually used for instance, peak plasma concentrations occur about 6 hours after a dose and the apparent elimination half-life may be 10 to 15 hours.

Renal impairment. Plasma-tamsulosin concentrations were reported to be increased in patients with renal impairment when compared with subjects with normal renal function. However, plasma concentrations of unbound, pharmacologically active drug were similar in both groups and it was suggested that the raised total plasma concentrations were due to an increase in plasma protein binding.

Uses and Administration

Tamsulosin is an alpha1-adrenoceptor blocker with actions similar to those of prazosin it is reported to be more selective for the alpha_1A-adrenoceptor subtype, which accounts for about 70% of the a₁ adrenoceptors in the prostate. It is used in benign prostatic hyperplasia to relieve symptoms of urinary obstruction.

In benign prostatic hyperplasia, tamsulosin hydrochloride is given orally in a modified-release formulation, in a dose of 400 micrograms once daily. Licensed US product information states that the dose may be increased after 2 to 4 weeks, if necessary, to 800 micrograms once daily.

Antidepressant-induced genito-urinary disorders. Tamsulosin was used successfully to treat urinary hesitancy observed in 6 male patients receiving reboxetine. Painful ejaculation associated with reboxetine was also treated successfully in 2 men.

Prostatitis. Alpha₁-adrenoceptor blockers are one of a number of classes of drugs that have been tried for symptomatic relief in men with chronic prostatitis. In a 6-week multicentre, double-blind placebo-controlled study involving 58 men with moderate to severe chronic prostatitis/chronic pelvic pain syndrome, tamsulosin 400 micrograms daily produced greater symptomatic relief than placebo the effect was considered clinically significant for men with severe prostatitis. The benefit appeared to take several weeks to develop, and it was considered possible that longer exposure would produce additional benefit.

Renal calculi. In the conservative management of renal calculi there is increasing interest in the possible use of drug treatment to ease the spontaneous passage of the stone down the ureter. Alpha₁-adrenoceptor blockers can decrease smooth muscle spasm in the ureter, reducing obstruction and improving urine flow. In studies of patients with uncomplicated lower ureteral stones, tamsulosin has been reported to improve the rate of stone expulsion and expulsion time, and to reduce analgesic requirements. Tamsulosin was generally given orally in a dose of 400 micrograms daily for up to 4 weeks. Comparison groups were treated with various other antispasmodics including benzodiazepines, phloroglucinol, and nifedipine in most studies patients were also treated with antibacterial prophylaxis, deflazacort, and NSATDs.

A review found evidence suggesting that adjunctive tamsulosin is safe and effective in enhancing the clearance of renal stones with a larger diameter when used with extracorporeal shock wave lithotripsy. Although evidence regarding ureteral stone clearance is inconclusive, adjunctive tamsulosin has been reported to reduce painful episodes.

Preparations

Proprietary Preparations

Argentina: Aclosan Controlpros Espontal Lostam Omnic Reduprost Secotex Tamsuna Tansiloprost

Australia: Flomax Flomaxtra

Austria: Alna

Belgium: Omic

Brazil: Contiflo Omnic Secotex Tamsulon

Canada: Flomax

Chile: Eupen Gotely Omnic Prostall Secotex Sulix Vi-Uril

Czech Republic: Apo-Tamis Damurgin Fokusin Lannatam Omnic Solesmin Taflosin Tamipro Tamsec Tamurox Tanyz Urostad

Denmark: Omnic

Finland: Expros Omnic Tamictor Tamsumin

France: Josir Omix

Germany: Alna Omnic

Greece: Omnic Pradif

Hong Kong: Harnal

Hungary: Fokusin Omnic Provosal Tamsol Tamsudil Tamsugen Tanyz Totalprost Urostad

India: Urimax

Indonesia: Harnal

Ireland: Omnexel Omnic Omsil Tamsu

Israel: Omnic

Italy: Omnic Pradif

Japan: Harnal

Mexico: Asoflon Secotex

The Netherlands: Mapelor Omnic

Norway: Omnic

New Zealand: Flomax Flomaxtra

Philippines: Harnal

Poland: Bazetham Fokusin Omnic Omsal Prostamnic Tamsudil TamsuLek Tanyz Uprox Urostad

Portugal: Omnic Pradif

Russia: Fokusin Hyperprost Omnic

South Africa: Flomax

Spain: Omnic Urolosin

Switzerland: Omix Pradif

Thailand: Harnal

Turkey: Flomax

United Kingdom: Bazetham Contiflo Flomaxf Flomaxtra Stronazon Tabphyn

USA: Flomax

Venezuela: Secotex Tamsulon

Multi-ingredient

India: Urimax  †

Summary

Symptoms of benign prostatic hyperplasia (BPH) are common in older men. They result from hyperplasia of glandular tissue and increased smooth muscle tone. Many men accept these symptoms as a normal part of the ageing process, and do not seek treatment.

As BPH is not always a progressive condition, and the incidence of complications is low, ‘watchful waiting’ is appropriate for men whose symptoms are mild.

Men suffering severe symptoms, or who develop complications of benign prostatic hyperplasia such as acute urinary retention or recurrent urinary tract infection, should be referred to a urologist for consideration of surgical treatment.

Transurethral resection of the prostate is the most commonly used surgical procedure. It is more effective than drug therapy, but is occasionally associated with complications such as impotence and incontinence.

Alphaj-adrenoceptor blocking drugs reduce smooth muscle tone in the prostatic tissue and bladder neck, decreasing resistance to urinary flow. They can produce cardiovascular side-effects, such as hypotension.

Tamsulosin (Flomax MR, capsules, 400 micrograms) is an inhibitor of the α_1A-receptor subtype, which is thought to be predominant in the prostate. No convincing evidence exists that this results in fewer adverse effects compared to other α₁-blockers.

Finasteride (Proscar, tablets, 5mg) inhibits 5α-reductase, resulting in shrinkage of prostatic glandular tissue. There is evidence that finasteride also reduces the risk of acute urinary retention and need for surgery, although such events are relatively uncommon.

Patients should be informed of the advantages and disadvantages of all treatment options, and should participate in the choice of therapy.

What is benign prostatic hyperplasia?

BPH is a benign enlargement of the prostate gland which occurs as a consequence of ageing. This leads to narrowing of the urethra, which may result in difficulty in passing urine. Prostatic enlargement is believed to be the result of two processes:

• hyperplasia of glandular tissue, under the stimulus of dihydrotestosterone (DHT); and

• increased smooth muscle tone, both within the prostate and in the bladder neck, under the control of α₁-adrenoceptors.

Medical treatment of benign prostatic hyperplasia aims to alter these processes, either by inhibiting 5α-reductase, the enzyme responsible for the formation of DHT, or by blockade of α₁-adrenoceptors.

Patients suffering from BPH may present with a variety of the following symptoms, which may be classified as:

• ‘filling’ symptoms: such as frequency, urgency, and nocturia; or

• ‘voiding’ symptoms: e.g. poor urinary stream, intermittent stream, hesitancy and terminal dribbling.

Symptoms from either or both categories may occur. While they may be irritating, these symptoms do not in themselves have serious consequences. However, on some occasions, bladder outflow obstruction resulting from benign prostatic hyperplasia may lead to recurrent urinary tract infection (UTI) and pyelonephritis, or chronic urinary retention and hydronephrosis.

How common is it?

Symptoms of BPH may be found in a large number of men over the age of 60, and the prevalence rises with age. There is a lack of consensus on an exact definition for the condition; differences in criteria for the diagnosis of benign prostatic hyperplasia have led to varying estimates of prevalence in studies.

One study determined the prevalence rates of BPH in a population of 502 men aged 55 to 74 using several different case definitions. Prevalence rates in men aged 60-64 varied from 2% to 22%, depending on the parameters used. In this study, the prostate volume used as the main cut-off for diagnosis of BPH was 30cm. However, in a study using a prostate weight of 20g as the cut-off, prevalence of benign prostatic hyperplasia in men aged 60-69 was 43%.

Added to this uncertainty is the fact that many men who admit to suffering symptoms of BPH when questioned, say their symptoms are not particularly bothersome. Many men accept symptoms of benign prostatic hyperplasia as a normal part of the ageing process, and may not be prompted to seek treatment.

What are the treatment options?

Treatment options for benign prostatic hyperplasia range from no active treatment (‘watchful waiting’), through various medical interventions, to surgical treatment. Each option is associated with a different balance of risks, benefits, and level of uncertainty about the long-term outcome. Treatment of BPH is directed at improving patients’ symptoms and quality of life rather than towards prevention of the serious morbidity or mortality which may rarely result. For these reasons, it is essential that patients are actively involved in the decision on which treatment they receive.

Non-drug treatment

Benign prostatic hyperplasia is not always a progressive condition. A review article summarising the results of five studies of the natural history of BPH, concluded that, of men with moderate symptoms followed for five years, 40% would improve, 45% remain unchanged and only about 15% deteriorate. One study randomly assigned 556 men with moderate symptoms of BPH to transurethral surgery or watchful waiting and followed them for almost three years. It found that only 7% of those assigned to the watchful waiting group required surgery for ‘treatment failure’. Watchful waiting is, therefore, considered a valid treatment option for men with mild to moderate symptoms.

Transurethral resection of the prostate (TURP) is considered to be the gold standard treatment for benign prostatic hyperplasia. It produces significant improvements for many men in symptoms and in objective measures, such as peak urinary flow rate. Complications which have been attributed to TURP include retrograde ejaculation, impotence, and some degree of urinary incontinence. However, the study mentioned above found no difference in rates of incontinence or impotence between men assigned to transurethral resection of the prostate and those assigned to watchful waiting.

Drug treatment

Alpha₁-adrenoceptor blocking drugs act by reducing smooth muscle tone in the prostatic tissue and bladder neck, thereby decreasing resistance to urinary flow. Six agents are available in the UK; these are alfuzosin (Xatral, tablets, 2.5mg; Xatral SR, tablets, 5mg), doxazosin (Cardura, tablets, 2mg/4mg), indoramin (Doralese, tablets, 20mg), prazosin (Hypovase, tablets, 2mg; Prazosin, tablets, 2mg), tamsulosin (Flomax MR, capsules) and terazosin (Hytrin BPH, tablets, 5mg/10mg).

A review of twenty-nine clinical trials of α₁-blockers stated that the average improvement in maximum urine flow rate (Qmax) with these compounds was 1.5ml/s. Overall symptom scores decreased by 14% and residual urine volume decreased by 29%. Some tolerance to the effects on urinary flow rate was noted in a proportion of patients after six months of therapy. However, the improvement in symptom scores was maintained long-term.

Side-effects associated with the α₁-blockers include hypotension, particularly after the first dose, sedation, and dizziness. Therapy is usually begun with a low dose taken at bedtime and titrated upwards over a few weeks.

Tamsulosin is an agent which is more selective than other alpha1-blockers; it is said to act on the α_1A-receptor subtype, which is thought to be predominant in prostatic tissue. Theoretically, such a selective action might avoid some of the cardiovascular effects seen with other agents.

Tamsulosin has been compared to alfuzosin and terazosin in clinical trials. When compared to alfuzosin in 245 men with benign prostatic enlargement and lower urinary tract symptoms suggestive of benign prostatic hyperplasia, tamsulosin produced comparable improvements in O and symptom scores over twelve weeks. Although tamsulosin had significantly less effect on both systolic and diastolic blood pressure than alfuzosin, no difference in the rate of adverse events associated with the hypotensive effects of α₁-blockers was observed.

In the second study, which was single-blind, involved 72 patients and lasted for nine weeks, tamsulosin and terazosin were similarly effective in improving both subjective and objective measures of BPH. The incidence of adverse cardiovascular effects was higher in the terazosin group. It is difficult to assess how relevant the results of this study are to the UK, as it was conducted in Korea and the dose of tamsulosin was much lower than that used here.

Finasteride is a specific inhibitor of the enzyme 5a-reductase, which is responsible for the metabolism of testosterone to dihydrotestosterone, a more potent androgen. DHT stimulates prostatic growth and the development of benign prostatic hyperplasia. Treatment with 5mg finasteride for twelve months has been shown to reduce prostate volume by 19%, increase maximum urinary flow rate by 1.6ml/s, and decrease total urinary-symptom scores by 21%.

Two recent studies investigated the effects of finasteride on the incidence of acute urinary retention and the need for surgical treatment. The first study was a pooled analysis of three randomised, double-blind, multicentre studies comparing finasteride 5mg daily to placebo over 24 months in 4,222 patients with moderate symptoms of BPH. Finasteride therapy was associated with a statistically significant reduction in both acute urinary retention and rates of surgical intervention.

The second study compared 5mg of finasteride to placebo over four years in a randomised, double-blind trial. A total of 3,040 men with enlarged prostates and moderate to severe urinary symptoms were recruited from 95 centres. The primary end-point of the study was the symptom score; need for prostate surgery and development of acute urinary retention were secondary end-points.

Symptom scores decreased by a mean of 3.3 points out of 35 (9.4%) in the finasteride group, compared to a mean of 1.3 points (3.7%) in the placebo group. The risks of surgery and acute urinary retention (AUR) were both significantly reduced by finasteride. However, the absolute reduction in the risk of surgery or AUR was only 6.6%, meaning that 15 men would have to be treated with finasteride for four years in order to avoid one episode of acute urinary retention or surgery.

A recent meta-analysis of six trials comparing finasteride with placebo examined whether there was any relationship between measures of disease severity at the start of treatment and the response to finasteride. It concluded that improvements in peak urinary flow rate and symptom scores were significant only in men whose prostate volume was measured (by ultrasound or magnetic resonance imaging) at greater than 40cm3.

Adverse effects associated with finasteride include decreased libido, decreased ejaculate volume and impotence. Finasteride reduces serum concentrations of prostate specific antigen (PSA), a marker for prostate cancer, by an average of 50%.

Finasteride was compared to terazosin, combination therapy, and placebo in 1,229 men in a double-blind study lasting 52 weeks. This study found that terazosin was significantly more effective than finasteride and placebo in improving symptom scores and urinary flow rate. It also found that the combination of terazosin and finasteride was no more effective than terazosin monotherapy, even though finasteride reduced prostate size. Finasteride alone was not significantly different to placebo.

This study has been criticised on the basis of its inclusion criteria, which were based on symptoms rather than prostate size. The average prostate volume in the study population was only 37cm. An accompanying editorial suggested that men with larger prostates might respond differently to finasteride.

How should patients be managed?

The following investigations are recommended before any course of action is decided:

• full medical history,

• urinary symptom review,

• digital rectal examination (DRE),

• urine analysis, and

• serum creatinine.

Routine measurement of serum prostate specific antigen (PSA) levels is controversial. This is due to uncertainty over whether moderately raised levels are indicative of benign prostatic hyperplasia or prostate cancer. GPs should discuss policies on the use of PSA levels with local urology departments.

Symptom severity is not directly related to prostate size. Use of a validated symptom score, such as the International Prostate Symptom Score (IPSS), can help to categorise the severity of BPH, and monitor response to therapy.

Referral to a urologist for further investigations (such as ultrasound and urinary flow rate studies) and management may be considered for patients with moderate to severe symptoms, as well as those with complications such as haematuria or recurrent urinary tract infection. Clinical suspicion of prostate malignancy should also prompt immediate referral.

Alpha1-blockers may be effective regardless of the size of the prostate. Full clinical response often occurs after 4-6 weeks, while finasteride may take 6 months or more to produce maximal effects. An α₁-blocker may, therefore, be an appropriate first choice therapy for many men, with finasteride reserved for those who do not tolerate α₁-blockade, fail to gain relief of symptoms, or whose prostates are known to be particularly enlarged. There is no convincing evidence that any α₁-blocker is more effective than another.

Conclusions

Although benign prostatic hyperplasia is common in older men, many consider the symptoms to be a normal part of the ageing process, and do not seek medical treatment. Given the variation in the natural history of the condition, and the uncertainty over the risks and benefits of most of the available interventions, there is no reason to encourage men who do not find their symptoms bothersome to seek medical intervention.

For those men whose symptoms are significantly bothersome, the use of a symptom scoring system in conjunction with clinical assessment will help to categorise severity. Those suffering from severe BPH should be offered the option of surgery, most likely by TURP. Those who decline surgery, or for whom it is not an option, may be offered drug therapy. Patients should be fully informed of the potential side-effects of all therapies, and should participate in the decision about which approach is taken.

Other Names for this Medication (Brand names): Flomax, Harnal, Omnic, Pradif, Tamsolusin, Tamsulosina [INN-Spanish], Tamsulosine [INN-French], Tamsulosinum [INN-Latin]

Appearance

Half orange-yellow and tan capsule marked with “FLOMAX 0.4 mg” on the orange side and “BI 58″ on the tan side.

Why this Medication is Used

Tamsulosin is used in the treatment of benign prostatic hyperplasia or BPH (enlargement of the prostate gland) by relaxing muscles in the prostate and bladder, resulting in improved urine flow and reduced BPH symptoms.

How do you take this Medication

The usual dose is 0.4 mg once per day but this may be adjusted by your doctor to 0.8 mg per day depending on the patient and/or severity of the symptoms of BPH. Tamsulosin may be taken 30 minutes following the same meal every day. If you interrupt your treatment for several days or more, resume treatment at one capsule/day, after consulting your doctor.

Precautions

• Make sure to schedule regular check-ups with your doctor while taking tamsulosin.

• Do not crush, chew or open capsules of tamsulosin, as the capsules are specially made to regulate the release of tamsulosin into the blood stream.

• Avoid driving or operating dangerous machinery for 12 hours after the initial or any increase in dose until you know how this medication will affect you.

• Tell your doctor if you are taking any of the following medications: Blood pressure lowering agents, Cimetidine and Warfarin.

• Store in a cool dry place at room temperature. Keep out of reach of children.

For more information on this medication, please call your doctor, pharmacist or nurse.

Generic Name Drug: Alfuzosin HCl

Company: Sanofi-Synthelabo

Indication / Use: Benign prostatic hyperplasia

Approval Date / FDA Class: 12 06 2003 / 1S

Development and Mechanism of Action:Benign prostatic hyperplasia (BPH) is defined histologically. Clinically, it is characterized by lower urinary tract symptoms (urinary frequency, urgency, a weak and intermittent stream, needing to strain, a sense of incomplete emptying, and nocturia) and can lead to complications, including acute urinary retention. The mechanisms by which BPH causes symptoms and complications are unclear, although obstruction of the bladder outlet is an important factor. The best documented risk factors are increasing age and functioning testes. Estimates of the prevalence of symptomatic BPH indicate that approximately 50% of men ages 51 to 60 have benign prostatic hyperplasia. Community- and practice-based studies suggest that men with lower urinary tract symptoms can expect slow progression of the symptoms. However, symptoms can wax and wane without treatment. In men with symptoms of BPH, rates of acute urinary retention range from 1% to 2% a year. The objective of drug therapy of BPH is to reduce or alleviate lower urinary tract symptoms, to prevent complications, and to minimize adverse effects of treatment.

Pharmacotherapy for benign prostatic hyperplasia includes the 5-alpha-reductase inhibitor finasteride (Proscar), and alpha₁-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. Androgen receptor antagonists are of no value in BPH because of their adverse effects. Smooth muscle tone in the prostate and bladder neck is regulated by alpha₁-adrenergic receptors. Blockade of these receptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of benign prostatic hyperplasia. Currently available alpha₁-adrenoceptor antagonists appear to possess very similar clinical efficacy producing a 15% to 25% increase in maximum flow rate with a significant improvement in 30% to 40% of patients. The non­tissue selective alpha₁-blockers (prazosin, terazosin, and doxazosin) can elicit postural symptoms related to orthostatic hypotension and they may cause episodes of dizziness and somnolence as a result of distribution to and action in the CNS. Uroselective alpha₁-blockers dosed on a once-daily schedule, tamsulosin (Flomax) and, most recently, alfuzosin, have been developed to address the drawbacks of the nonselective agents.

Alfuzosin (UroXatral), a tetrahydroquinazoline derivative, differs from the non­tissue selective alpha1-blockers as a result of replacement of the piperazine heterocycle in the latter with a propylenediamine moiety in the structure of the new drug. Alfuzosin is not selective for any of the alpha₁-adrenoceptor subtypes (A, B, or D) but has been shown to possess a high selectivity for receptors in the lower urinary tract. At doses three to 10 times higher than those required to induce significant urethral relaxation in animal models, alfuzosin shows the lowest and shortest-lasting hypotensive activity compared to doxazosin, tamsulosin, and terazosin. Pharmacokinetics: A comparison of selected pharmacokinetic parameters of the alpha₁-adrenoceptor antagonists is provided in table 1. The oral absorption of alfuzosin is significantly aided by the presence of food. The drug is extensively cleared by hepatic metabolism primarily involving the 3A4 isoform. Excretion of the drug and metabolites occurs mainly in the feces.

While there is no relationship between peak plasma concentrations of alfuzosin and age, trough levels are positively correlated with age. The concentrations in subjects 75 and older are approximately 35% greater than in those below age 65. Relative to subjects with normal renal function, the mean C_max and AUC values for alfuzosin are increased by approximately 50% in patients with mild, moderate, or severe renal impairment. Clearance of alfuzosin is reduced in patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), leading to threefold to fourfold higher plasma concentrations of the drug in these patients compared to healthy subjects. Therefore, alfuzosin is contraindicated in patients with moderate to severe hepatic impairment.

UroXatral: Clinical Profile

Alfuzosin (UroXatral) is officially indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. Clinical efficacy data for alfuzosin from placebo-controlled trials have demonstrated efficacy compared to placebo in urinary flow improvement and in improvement in urinary symptoms without the need for dose titration. A randomized controlled clinical trial in 256 men compared tamsulosin against alfuzosin while a second trial in 103 men compared alfuzosin against prazosin in the treatment of BPH. These trials found no significant difference in symptom score among a-blockers tested. A clinical trial in 1,051 men comparing alfuzosin against finasteride against both drugs combined over six months found that alfuzosin compared with finasteride significantly decreased the mean international prostate symptom score from baseline, and found no significant difference between alfuzosin alone and combination therapy.

Adverse Reactions

In the clinical trials, the most common adverse effects occurring more frequently than with placebo were dizziness, upper respiratory tract infection, headache, and fatigue. Withdrawals attributed to adverse events have been found to be similar for alfuzosin, tamsulosin (0.4-mg dose), and placebo. However, a higher withdrawal rate was found with doxazosin, terazosin, and tamsulosin (0.8-mg dose). There was little observable difference between the number of men experiencing dizziness with alfuzosin or tamsulosin compared with placebo. However, more men experienced dizziness after terazosin and doxazosin than placebo. Comparison of tamsulosin versus alfuzosin found similarities in the incidence of common adverse effects including dizziness (7%), asthenia (2%), and postural hypotension (2%).

As with other a-blockers, some patients may experience postural hypotension or syncope. If symptoms of angina pectoris should appear or worsen, the use of alfuzosin should be discontinued. Caution should be exercised when alfuzosin is administered in patients with severe renal insufficiency. Consideration should be given in deciding to prescribe alfuzosin for patients with a known QT prolongation or who are taking medications known to prolong QT, although there has been no signal of torsades de pointes in extensive postmarketing experience with alfuzosin outside the United States.

Drug Interactions

Clearance of alfuzosin (UroXatral) via CYP3A4 metabolic pathways results in interactions between the new drug and other drugs that either inhibit or induce this enzyme. Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax 2.3-fold and AUC increased 3.2-fold following a single 10-mg dose of alfuzosin. Therefore, alfuzosin should not be coadministered with potent inhibitors of CYP3A4, eg, ketoconazole, itraconazole, or ritonavir, because exposure is increased. Coadministration of alfuzosin with antihypertensive medications may enhance the effects of the latter on blood pressure.

Dosage and Administration

UroXatral (alfuzosin) hydrochloride is formulated as a 10-mg extended release tablet. The recommended dosage is one 10-mg extended-release tablet daily to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

An important issue is extrapolation of the results of alfuzosin (Uroxatral) to the terazosin (Hytrin) we prescribe in Canada. Although the affinity αa/αb receptor ratio is similar for alfuzosin and terazosin, their incidence of association with signs of hypotension differ. In placebo-controlled trials, patients treated with terazosin experienced obvious signs of hypotension, whereas incidence among patients receiving tamsulosin (Flomax) and alfuzosin (Uroxatral) was similar to that among patients treated with placebo. This indirect comparison between α-blockers has, of course, important limitations but should be borne in mind when extrapolating results to terazosin (Hytrin).

Two trials have directly compared tamsulosin (Flomax) with terazosin (Hytrin). One single-blind trial was conducted among Asian men with high-normal blood pressure levels and symptomatic benign prostatic hyperplasia (BPH). They received 0.2 mg of tamsulosin (half the dose white men would receive) or 5 mg of terazosin daily. Both groups experienced significant improvement in Qmax and symptom scores, but the number of side effects and the reduction in standing blood pressure levels from baseline (-16.1/-11.4 mmHg for the terazosin group vs -9.4/-5.4 mmHg for the tamsulosin group) was statistically greater in the terazosin group. The authors did not mention whether lowering blood pressure levels had an effect on symptoms. The other trial included normotensive healthy men, only half of whom had BPH. Patients were randomized in a double-blind fashion to receive 0.4 mg of tamsulosin (Flomax) or 5 mg of terazosin (Hytrin) daily. Significantly more patients treated with terazosin experienced symptomatic hypotension, but there was no difference in the proportion of patients experiencing asymptomatic hypotension. No differences were observed in blood pressure. These two studies have several important limitations, namely the smaller tamsulosin dose used and the fact that some patients did not have benign prostatic hyperplasia. The results, however, when interpreted with results of the placebo-controlled trials, support some of the findings of the alfuzosin-tamsulosin trial. These findings include a lower incidence of signs of hypotension in normotensive and hypertensive patients receiving tamsulosin and, possibly, no significant decrease in blood pressure in patients with high-normal (or stage 1) hypertension in the tamsulosin group.

Several categories of patients with symptomatic BPH can present a treatment dilemma: hypertensive patients already stabilized using other antihypertensive medications, normotensive patients, normotensive patients receiving other antihypertensive agents for other indications (eg, an angiotensin-converting enzyme inhibitor [ACE-I] for diabetic nephropathy), and patients for whom suboptimal doses of α-blockers reduce benign prostatic hyperplasia symptoms but cause hypotensive side effects. For these patients, an attempt to initiate or reinstitute a non-selective α-blocker with more frequent follow-up visits and a very slow titration of dose could be tried, or tamsulosin could be initiated, provided patients can afford it (approximately $36/month). The costs of tamsulosin (Flomax) and terazosin (Hytrin) are similar, but only terazosin is covered on most provincial drug plans.

Two important benefits can be derived from using tamsulosin (Flomax). First, because the dose does not need to be titrated, there is less risk of confusion for patients and fewer follow-up visits. Second, the possibility of a faster onset of action would mean a faster improvement in quality of life for patients.

Several questions, such as whether tamsulosin also has a favourable effect on lipids, whether it decreases risk of falls, and what its long-term effects are, remain unanswered.

Bottom line

• Tamsulosin (Flomax), a uroselective α-blocker, at a dose of 0.4 mg, appears to be as effective as alfuzosin (Uroxatral), a non-selective α-blocker. Unlike terazosin (Hytrin), the dose of tamsulosin does not need to be titrated. Tamsulosin (Flomax) produced slightly fewer symptoms of hypotension, but this did not translate into clinical outcomes, such as more falls. These benefits might not be important because terazosin is now available in starter packs to assist patients to titrate the dose themselves.

• Patients who already have good blood pressure control with other preferable agents (eg, diabetics receiving ACE-Is) and who had severe hypotensive effects with non-selective α-blockers might prefer a uroselective agent.

• Most of our patients with benign prostatic hyperplasia are also at risk for hypertension, and a non-selective α-blocker treats both conditions with one pill. Differences between the two treatments were small, and patient-oriented outcomes were similar.

• Tamsulosin (Flomax) is slightly more expensive and does not seem to confer greater benefits for most of our patients.

Symptomatic benign prostatic hyperplasia (BPH) is a common condition encountered in about 50% of male patients older than 50. Prevalence increases with age. In the last few years, pharmacologic treatment and watchful waiting have played an increasing role in treating symptomatic BPH. Until recently, pharmacologic options were limited to non-selective α-blockers and finasteride (Proscar). Non-selective α-blockers are usually first-line agents because their onset of action is fast (4 to 6 weeks); their efficacy is maintained, especially in patients with smaller prostates; and they are not expensive. Non-selective α-blockers, initially developed to treat hypertension, can cause side effects, such as postural hypotension, dizziness, headache, palpitations, and syncope.

Tamsulosin (Flomax), a selective α-blocker, has been commercially available in Canada since June 1998. Because it is more urospecific than other α-blockers, it has less potential for causing symptomatic hypotension. The dose of tamsulosin does not need to be titrated and this might, therefore, decrease the frequency of follow-up visits and result in a faster onset of action. In this trial, tamsulosin is compared with alfuzosin (Uroxatral), which is roughly comparable to the terazosin (Hytrin) commonly prescribed in Canada.

Overview of study and outcomes

A total of 245 men at least 45 years old entered the study. Main inclusion criteria were a Boyarsky score >6 and a maximum urinary flow (Qmax) of <12mL/s and >4mL/s.

The Boyarsky system score is a symptom-assessment tool used to evaluate the severity of nocturia, frequency, hesitancy, intermittency, terminal dribbling, urgency, impairment of size and force of stream, dysuria, and sensation of incomplete voiding. The system allows 0 to 3 points for each of nine questions for a maximum of 27 points. Patients scoring < 7 points are considered mildly symptomatic; 8 to 19 points moderately symptomatic; and > 20 points severely symptomatic.

Main exclusion criteria for the trial were coexisting conditions affecting micturition, previous pelvic region surgery, and concomitant medications acting on the prostate (eg, anticholinergic drugs). After a 2-week placebo run-in period, patients were randomized to alfuzosin (n = 119) or tamsulosin groups (n = 126). Primary outcome variables, Qmax, and total Boyarsky score were measured at weeks 2, 6, and 12. Secondary outcome variables included irritative, obstructive, and individual symptom Boyarsky score; tolerability; and lifestyle issues. Intention-to-treat analysis was performed, and all statistical tests were two-sided.

Results

Tamsulosin (Flomax) and alfuzosin (Uroxatral) had similar strong effects on Qmax, which increased by 1.6 mL/s, and on total Boyarsky score, which decreased by 4.1 and 3.8 points, respectively. Maximum urinary flow was achieved within 2 weeks with tamsulosin and between 2 and 6 weeks with alfuzosin.

For the secondary end points, no difference was observed in the lifestyle questionnaire score or Boyarsky obstructive, irritative, and individual symptom scores between the two groups. Hypotensive effects, such as dizziness, headaches, palpitation or tachycardia, syncope, and postural hypotension, were experienced by 9.2% of patients in the tamsulosin group and 10.5% of patients in the alfuzosin group (P=.442). All other side effects, attributed to the drug or not, were not statistically significantly different between groups (53% vs 43%, P= .826).

At baseline in the tamsulosin group, mean supine blood pressure level was 143.9/85.7 mm Hg and mean standing blood pressure level was 141/88 mm Hg. At the end, there was no significant reduction of mean blood pressure levels in the tamsulosin group (-0.9 mmHg for supine and standing systolic blood pressure and +0.3 and -1.8 mmHg for supine and standing diastolic blood pressure). In the alfuzosin group, mean baseline supine blood pressure level was 146.1/88.5 mm Hg, and mean baseline standing blood pressure level was 142.9/88.6 mm Hg. A significant change from baseline in supine and standing systolic blood pressure level of-5.3 and -3.6 mm Hg, respectively, and in supine and standing diastolic blood pressure level of -3.6 and -4.5 mmHg, respectively, were observed. Differences between the groups were 4.4 mmHg for systolic and 2.7 to 3.9 mmHg for diastolic blood pressure level at end point (P≤.05). The authors did not explain whether these differences had an effect on symptoms.

Subgroup analysis showed that patients aged 65 or older (n=57) in the alfuzosin group experienced larger blood pressure level reductions than patients that age (n = 59) in the tamsulosin group. Changes of-0.1 to -1.0 in systolic and +0.6 to -0.8 in diastolic pressure levels were seen in the tamsulosin group; changes of -8.6 to -9.7 mmHg (systolic) and -5.4 and -6.2 mmHg (diastolic) were seen in the alfuzosin group. Differences in mean blood pressure levels from baseline to end point between the treatment groups were almost 9 mm Hg (systolic) and 5 mm Hg (diastolic) (P= .016). Normotensive patients in the alfuzosin group had greater supine blood pressure level reductions than those in the tamsulosin group (P=.029). Again, the authors did not elaborate whether these differences were in symptoms. No significant differences between the two treatment arms could be observed in patients younger than 65 years (n= 131) or in hypertensive patients (n=59).

Analysis of methodology

The study was well designed, but the omission of use ful information made it difficult to interpret and apply the results to a specific patient population. For example, patients’ baseline characteristics were not reported, and the lifestyle questionnaire was not described. Also, the exact onset of action of tamsulosin (Flomax) could not be determined because the first follow-up visit was 2 weeks after initiation of treatment. Finally, measuring patients’ and their partners’ satisfaction would have been helpful for using the results in the context of clinical practice.

Benign prostatic hyperplasia (BPH) is a condition that results in proliferation of the stromal/epithelial cells of the prostate gland. This proliferation produces related symptoms such as dysuria, urinary retention, urinary obstruction, and urgency. The prevalence of BPH is age-dependent; approximately 66% of men older than age 65 show some symptoms.

Currently available treatment for the management of BPH includes alpha- antagonists, 5-alpha-reductase inhibitors, antiandrogens, and gonadotropin-releasing hormone analogs. Tamsulosin, which is an alpha-1A-adrenoreceptor antagonist, has been studied for use in the treatment of BPH.

How It Works

There is a large quantity of alpha-1 adrenoreceptors in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Three subtypes of alpha receptors have been identified in the human prostate — alpha-1a, alpha-1b, and alpha-1d. Of these three, alpha- 1a is the predominant subtype. Tamsulosin (Flomax) is an alpha-1A-adrenoreceptor antagonist; it causes a blockade of the receptors, resulting in smooth muscle relaxation in the prostate and bladder neck. This relaxation, in turn, causes an improvement in the urinary flow rate and a reduction in the symptoms of BPH.

Flomax: Clinical Tips

An open-label extension study, as well as other trials, concluded that tamsulosin is safe and effective in the treatment of BPH. The only known associated side effects are abnormal ejaculation and dizziness. This extension study will continue for another 4 years to determine if the safety and efficacy profile can be maintained on a long-term basis.

Over 90% of tamsulosin (Flomax) is absorbed following oral administration of a 0.4-mg dose under fasting conditions. Tamsulosin is extensively bound to protein. Administration of tamsulosin with food causes a 30% decrease in bioavailability and increased time to maximal plasma concentration. Tamsulosin is extensively metabolized by the liver; only about 10% is excreted via the urine as unchanged drug.

Flomax (tamsulosin) has certain advantages over other alpha-antagonists that are used in the treatment of benign prostatic hyperplasia. Because of its specificity for alpha-1a receptors, it seems to leave alpha receptors in the blood vessels alone. Hence, it is associated with less orthostasis than are other alpha-antagonists. Also, there is no need to titrate tamsulosin to the recommended dose, as with other alpha-antagonists, which must be initiated at lower doses, then increased gradually to avoid first-dose syncope and orthostasis. Tamsulosin is widely used in Europe. If things go well, it may become the drug of choice in the treatment of BPH in the United States as well.