Alternative to BPH Surgery

New Xatral formulation allows once-daily dosing with effective relief of symptoms and few side effects

While surgery remains the ultimate management option for benign prostatic hyperplasia (BPH), medical management has reduced the need for invasive procedures and become the first line of treatment especially in cases where surgery is risky or not possible because of conditions affecting the patient.

    Among several drugs in the market, alpha-adrenergic blockers are considered the choice medication. But these also come in several types of formulation--short-acting or long-acting, selective or non-selective. Alfuzosine (Xatral) is classified among the selective alpha-blockers whose new long-acting, extended release formulation was recently introduced.

    In a symposium organized by the Philippine Urological Association and Sanofi-Synthelabo, Dr. Christine Geffriaud-Ricouard, nephrologist and medical director for Xatral of Sanofi-Synthelabo in Paris, explained the drug's mechanism of action and benefits. She also presented preliminary results from the multicenter open-label international Alf-One Study designed to test the long-term efficacy and safety of alfuzosine 10 mg once-daily formulation.

    Results of the study are seen to have tremendous impact on the management of BPH, especially since this serious disorder affects the quality of life of at least half of the world's male population over 60 years old. An efficacious and safe medical treatment can possibly delay or prevent surgery while improving the quality of life of BPH patients. It will offer BPH patients a choice other than going under the knife.

Geomatrix Technology

    Xatral OD's innovative dose delivery system called Geomatrix Technology allows a sustained, constant, gradual release of the drug's active ingredient over 24 hours for optimum efficacy and consistent relief of symptoms with a single-dose and without need for titration.

    Dr. Ricouard said this was achieved by formulating Xatral into a three-layer tablet (Figure 1) that dissolves in three phases at specific time intervals until the drug is fully absorbed. She explained how it works.

    Once taken in, the tablet's first layer swells in the stomach in one to two hours, then gradually erodes and stays in the gut for about six hours. This stage of slow diffusion and erosion allows absorption of 30 percent of the drug. The tablet then moves into the small intestine where it stays for another six hours while the second layer disintegrates, allowing 40 percent absorption. Finally, the remaining third layer goes into the colon and dissolves, allowing absorption of the remaining 30 percent in six to eight hours.

Phased Absorption

    The phased dissolution enables one tablet to maintain 24 hours of efficacy without major fluctuations in plasma concentration. Dr. Ricouard said this has been shown in bioequivalence studies that compared Xatral OD with the earlier 2.5-mg tablet taken thrice daily and the 5 mg taken twice daily. "Xatral 10 mg once daily provides a plasma concentration time profile compatible with [that of] a once-daily formulation," said Dr. Ricouard.

    She added it also enhances the drug's safety compared with the three-day dosing because it avoids the three plasma concentration peaks that are associated with cardiovascular side effects.

    But Dr. Ricouard stressed that the drug should be taken on a full stomach to ensure efficacy. "While it is safe to take even on an empty stomach, it is not advisable because it loses its consistency and efficacy," she noted.

    Extensive clinical research has shown that flow rates with immediate release and once daily formulation of alfuzosine are improved by as much as 30 percent regardless of the prostate size. It is also the only alpha blocker that has "shown a significant improvement in residual urine compared with placebo at one, three, and six months," said Dr. Ricouard.

    Alfuzosine can effectively alleviate symptoms and improve quality of life. Studies have shown that 35 percent of patients have a moderate improvement in 12 months and the benefits may extend for up to three years. It has not been associated with retrograde ejaculation, impotence, or impairment of libido.

    As for its cardiovascular tolerability, Dr. Ricouard said alfuzosine shows a very low (less than one percent) incidence of postural hypotension, dizziness, and vasodilatory effects. These side effects commonly observed with non-selective alpha channel blockers are absent in alfuzosine owing to its uroselectivity.

ALF-One Study

    Xatral OD's long-term efficacy and safety is the subject of the on-going ALF-One Study that will run from six months to five years in 31 countries. About 8,000 patients are expected to be enrolled in the study.

    Reviewing the preliminary results of the first batch of 1,274 patients from France, Denmark, the Netherlands, and Switzerland, Dr. Ricouard noted the low total dropout rate of 4.3 percent.

    Based on the International Prostate Symptom Score (IPSS) system, low urinary tract symptoms (LUTS) were moderate for 63 percent of the patients and severe for 27 percent. Seventy-eight percent were moderately bothered while 16 percent were severely bothered.

    The study population profile indicated the following: 35 percent have been treated for hypertension, nine percent for ischemic heart disease, and three percent for heart failure; nine percent have had urinary tract infection, four percent have had microscopic hematuria, three percent have suffered acute urinary retention, and four percent have undergone surgery for BPH; and 37 percent have big prostates.

    Dr. Ricouard said the questionnaire results revealed that quality of life impairment is strongly related to LUTS severity, the prevalence of erectile and ejaculatory dysfunction increases with age and LUTS severity, and sexual dysfunction is bothersome for patients.

Preliminary Findings

    Dr. Ricouard reported that the percentage of patients who experienced severe symptoms at the start of the study dropped from 27 to nine percent while those who had moderate symptoms also decreased from 64 to 55 percent.

    Filling and voiding symptom scores also improved substantially from baseline (Figure 2). Significant improvements were noted in the quality of life as measured in daily living activities, wellbeing, and sexual activity. The percentage of those who had erection and ejaculation problems also dropped significantly.

    Dr. Ricouard said the drug was well tolerated with less than ten percent experiencing adverse events and only two percent reporting a serious adverse event. Dizziness was felt by 2.7 percent of patients. Headache, malaise, hypotension, abnormal ejaculation, somnolence, asthenia, and fatigue were insignificant. Among the hypertensive patients, a very low 2.5-percent reported vasodilatory-related events compared with 1.6 percent for normotensive patients.

    Only three patients had acute urinary retention and five underwent surgery.

    Summing up, Dr. Ricouard said Xatral OD is effective and well-tolerated. The low incidence of vasodilation-related events guarantees safe use even for patients at risk. It did not cause sexual dysfunction.