Health and Prostate

Trade Name Drug: UroXatral

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.