FDA-Approved Indications and Clinical Efficacy
The Food and Drug Administration (FDA) is reviewing an ER formulation of alfuzosin hydrochloride 10 mg for once-daily administration for treatment of symptomatic BPH. The IR and twice-daily ER preparations will not be available in the United States, although they are currently available in Europe.
Patients with moderate to severe symptoms of BPH (also known as lower-urinary-tract symptoms) will exhibit obstructive voiding symptoms, including decreased force of urinary stream, urinary hesitancy, straining to void, incomplete bladder emptying, urinary dribbling, or urinary stream intermittency. They may also complain of irritative voiding symptoms if they have had longstanding BPH with chronic bladder outlet obstruction and compensatory bladder hypertrophy. Irritative voiding symptoms include urinary urgency, clothes wetting or bedwetting, dysuria, increased daytime urinary frequency, and nocturia. The α1-adrenergic antagonists reduce excessive α-adrenergic tone in the stromal portion of the prostate gland, prostatic capsule, and bladder neck urethra. Thus, smooth muscle relaxes and the caliber of the urethral lumen enlarges, enabling bladder emptying. Obstructive voiding symptoms are relieved and in some cases irritative bladder symptoms also improve, possibly as a result of improved bladder emptying. It is important to note that α1-adrenergic antagonists do not directly restore detrusor muscle contractile function, the cause of irritative voiding symptoms.
When directly compared with placebo, α1-adrenergic antagonists significantly increase peak and mean urinary flow rates by 15-30%, variably decrease postvoided residual urine volume, and improve obstructive and irritative voiding symptoms by 30-50% when measured using standardized instruments (e.g., Boyarsky Symptom Scoring System, American Urological Association Symptom Index, or International Prostate Symptom Score.[31,32,33,34,35,36]
Alpha-1-adrenergic antagonists are recommended for the treatment of moderate to severe BPH. These agents are effective independent of the size of the prostate, leading to symptom improvement in 30-40% of patients. Approximately 30% of patients experience at least a 30% increase in peak urinary flow rate. The usual improvement in peak urinary flow rate is 16-25%. Patients with more severe symptoms have a greater response to treatment than those with milder symptoms. Onset of action for these agents occurs within hours, but peak effect is reached in two to four weeks. In the case of terazosin and doxazosin, the delay in peak onset is due to dosage adjustments, which are necessary to minimize orthostatic hypotension. Durable treatment responses have been documented for up to four years. Although drug treatment does not cure the patient of the disease, it delays disease progression and the need for surgical intervention. However, not all patients respond to therapy. Non-responders may have BPH attributable to mechanical obstruction of the bladder neck and urethra by an enlarged prostate as opposed to excessive adrenergic stimulation of the prostatic stoma.
Alpha-1 adrenergic antagonists have comparable effectiveness in treating moderate to severe symptoms of BPH. In a meta-analysis of placebo-controlled studies and direct comparison studies of 6333 patients, terazosin, doxazosin, alfuzosin, and tamsulosin were equally effective in improving voiding symptoms and increasing urinary flow rate. However, the frequency of adverse effects differs among these drugs. The discontinuation rates and frequency of adverse cardiovascular effects, including first-dose syncope, orthostatic hypotension, and dizziness, are higher with terazosin, doxazosin, and IR alfuzosin, lower with ER alfuzosin, and least with tamsulosin.[36,37] In addition, the highest rate of ejaculatory disorders has been reported with tamsulosin. In a direct comparison study with placebo, the frequency of drug-related ejaculation disorders with tamsulosin 0.4 mg daily and placebo was 4.5% and 0.5%, respectively. In a single direct comparison study, alfuzosin 2.5 mg administered thrice daily and tamsulosin 0.4 mg taken once daily caused 0% and 0.8% frequency of ejaculatory disorders, respectively.
Reports from many clinical trials have been published about using alfuzosin for the management of symptomatic BPH. Between 40% and 70% of patients with BPH who were treated with placebo have reported symptom relief. In addition, BPH symptoms have improved or stabilized in patients who have received no treatment, as found in one meta-analysis in which 38% of patients' voiding symptoms had improved at 2.6 to 5.0 years follow-up despite not receiving any treatment for BPH. An excellent review of the published literature that summarizes the results of randomized controlled clinical trials with α1-adrenergic antagonists has been recently published. Table 2 and Table 3 summarize some of these studies. The tables compare improvements in voiding symptoms as assessed using various standardized scoring systems and peak urinary flow rate (milliliters per minute) of alfuzosin versus placebo, which are consistent with those reported in various meta-analyses.
Alfuzosin Studies. The effect of alfuzosin on postvoided residual urinary volume has been recently assessed in a meta-analysis of 11 double-blind controlled studies of 953 evaluable patients who received alfuzosin 2.5 mg thrice daily or ER alfuzosin 5 mg twice daily versus placebo for one to six months. At baseline, all patients had a postvoided residual urinary volume between 50 and 350 mL. Alfuzosin-treated patients had a significant decrease in postvoided residual urinary volume, greater than that seen with placebo (p < 0.01). The rate of acute urinary retention was less with alfuzosin than placebo (0.3% and 1.4%, respectively). Reduction in postvoided residual urinary volume is a direct extension of alfuzosin's effect on the bladder neck and prostate to enhance bladder emptying. Additional clinical studies are needed to determine if alfuzosin can lower a patient's risk for developing complications of BPH, including calculi, urinary tract infection, and renal failure.
Short-course two-day treatment with alfuzosin has been used as an interim measure following urethral catheterization for acute urinary retention to allow a successful trial without catheterization (TWOC). In these patients, a successful TWOC before surgical intervention could allow time for a full diagnostic workup and reduce the need for catheter reinsertion because of a repeated episode of acute urinary retention. In a study of 81 patients, 55% of patients treated with alfuzosin 5 mg twice daily, starting 24 hours before the TWOC and continuing for 24 hours after catheter removal, had a successful TWOC; 68% of patients with a successful TWOC did not have a second episode of acute urinary retention within the mean follow-up period of 7.2 months. However, 4 of 40 alfuzosin-treated patients had adverse effects, which was more than in the placebo group. These adverse effects included first-dose syncope, headache, dizziness, and arrhythmias.[50,51]
Long-Term Therapy with Alfuzosin. Alfuzosin produces durable treatment responses in patients with BPH. To date, the longest follow-up period has been three years. In that study, Lukacs et al. followed 2579 patients who were treated with 2.5 mg of alfuzosin three times a day. The percentage of patients requiring surgical intervention decreased or remained stable during the follow-up period, consistent with the belief that drug therapy may delay the development of BPH complications. Jardin et al. followed patients for 24-30 months and found that voiding symptoms and urinary flow rate improvements after long-term use were similar to those of shorter-term studies. Thus, the beneficial effects of alfuzosin are maintained with continued treatment.
ER versus IR Alfuzosin. ER alfuzosin is administered once or twice daily, enhances patient compliance, and is associated with fewer adverse cardiovascular effects than IR alfuzosin. Buzelin et al. found that ER alfuzosin 5 mg twice daily was similar to placebo in the rates of drug-induced adverse cardiovascular effects. However, in elderly and hypertensive patients, ER alfuzosin was associated with a higher cumulative frequency of asymptomatic orthostatic hypotension than placebo-treated patients. In another report, Buzelin et al. compared ER alfuzosin 5 mg twice daily with placebo. The number of patient dropouts due to adverse effects was similar between both groups. ER alfuzosin did not cause first-dose syncope in any patient, probably because the ER formulation produced little fluctuation in serum alfuzosin concentrations over the dosing interval and relatively stable serum concentrations were maintained between doses.[30,47,48,54]
Van Kerrebroeck compared the efficacy and safety of 10 mg of ER alfuzosin given once daily without any dosage adjustment with 2.5 mg of IR alfuzosin thrice daily and placebo for three months, followed by an open-label extension period of up to one year. The three-month treatment portion of the study found that both formulations were equally effective in increasing peak urinary flow rate and improving patients' voiding symptom score and that both formulations were more effective than placebo. However, IR alfuzosin caused more vasodilatory adverse effects than the ER formulation (9.4% versus 3.4%), respectively. A greater percentage of patients treated with the IR drug discontinued treatment compared with those treated with the ER formulation (3.4% versus 1.4%, respectively).
Am J Health Syst Pharm. 2003;60(14) © 2003 American Society of Health-System Pharmacists
Cite this: Alfuzosin Hydrochloride for the Treatment of Benign Prostatic Hyperplasia - Medscape - Jul 15, 2003.