Alfuzosin

Pharmacotherapeutic group: urologicals, alpha-adrenoreceptor antagonists, ATC code: G04CA52 Dutasteride/tamsulosin is a combination of two active substances: dutasteride, a dual 5-α-reductase inhibitor (5-ARI), and tamsulosin hydrochloride, an α1a- and α1d-adrenoceptor antagonist. These two active substances have complementary mechanisms of action that rapidly relieve disease symptoms, improve urinary flow, and reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery. Dutasteride inhibits both isoenzymes of 5-α-reductase (types 1 and 2), which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostatic growth and the development of BPH. Tamsulosin inhibits α1a- and α1d-adrenergic receptors in the smooth muscle of the prostate and bladder neck. Approximately 75% of α1 receptors in the prostate are of the α1a subtype. Coadministration of dutasteride and tamsulosin The following statements reflect information available from combined treatment with dutasteride and tamsulosin. In a four-year, multicentre, international, randomised, double-blind, parallel-group study, dutasteride 0.5 mg/day (n=1,623), tamsulosin 0.41 mg/day (n=1,611), or the combination of dutasteride 0.5 mg with tamsulosin 0.4 mg (n=1,610) were evaluated in male subjects with moderate-to-severe BPH symptoms, a prostate volume ≥30 ml, and PSA values in the range 1.5–10 ng/ml. Approximately 53% of subjects had previously been treated with a 5-alpha-reductase inhibitor or an alpha1-adrenoceptor antagonist. The primary efficacy endpoint over the first two years of the study was change in the International Prostate Symptom Score (IPSS), an eight-item questionnaire based on the AUA-SI with an additional question on quality of life. Secondary efficacy endpoints at 2 years included maximum urinary flow rate (Qmax) and prostate volume. For change in IPSS, combination therapy achieved significant improvement versus dutasteride from Month 3 and versus tamsulosin from Month 9. For change in Qmax, combination therapy achieved significant improvement versus both dutasteride and tamsulosin from Month 6. The combination of dutasteride and tamsulosin produces a greater reduction in symptoms than either active substance alone. After two years of treatment, coadministration demonstrated a statistically significant mean improvement in symptom score from baseline of -6.2 points. The adjusted mean improvement in urinary flow rate from baseline was 2.4 ml/s with coadministration, 1.9 ml/s with dutasteride, and 0.9 ml/s with tamsulosin. The adjusted mean improvement in the BPH Impact Index (BII) from baseline was -2.1 points with coadministration, -1.7 with dutasteride, and -1.5 with tamsulosin. With coadministration, these improvements in urinary flow rate and BII were statistically significant compared with each monotherapy. The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant with coadministration compared with tamsulosin monotherapy. The primary efficacy endpoint at 4 years of treatment was the time to the first occurrence of AUR or the need for BPH-related surgery. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% risk reduction, p<0.001 [95% CI 54.7% to 74.1%]) compared with tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% in the combination group and 11.9% with tamsulosin (p<0.001). Compared with dutasteride monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6% (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 with dutasteride was 5.2%. Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS worsening ≥4 points, BPH-related AUR, incontinence, urinary tract infection (UTI), and renal insufficiency), change in IPSS (International Prostate Symptom Score), maximum urinary flow rate (Qmax), and prostate volume. The IPSS is an 8-item questionnaire based on the AUA-SI with an additional question on quality of life. Results after 4 years of treatment are summarised below: Parameter Time point Combination Dutasteride Tamsulosin AUR or BPH-related surgery (%) Incidence at 48 months 4.2 5.2 11.9a Clinical progression* (%) Month 48 12.6 17.8b 21.5a IPSS (units) [baseline] Month 48 (change from baseline) [16.6] -6.3 [16.4] -5.3b [16.4] -3.8a Qmax (ml/s) [baseline] Month 48 (change from baseline) [10.9] 2.4 [10.6] 2.0 [10.7] 0.7a Prostate volume (ml) [baseline] Month 48 (% change from baseline) [54.7] -27.3 [54.6] -28.0 [55.8] +4.6a Prostate transition zone volume (ml)# [baseline] Month 48 (% change from baseline) [27.7] -17.9 [30.3] -26.5 [30.5] 18.2a BPH Impact Index (BII) (units) [baseline] Month 48 (change from baseline) [5.3] -2.2 [5.3] -1.8b [5.3] 0.7a IPSS Question 8 (BPH-related health status) (units) [baseline] Month 48 (change from baseline) [3.6] -1.5 [3.6] -1.3b [3.6] -1.1a Baseline values are mean values, and changes from baseline are adjusted mean changes. * Clinical progression was defined as a composite of: IPSS worsening ≥4 points, BPH-related AUR, incontinence, UTI, and renal insufficiency. # Measured at selected centres (13% of randomised patients). Combination therapy reached statistical significance (p<0.001) versus tamsulosin at Month 48. Combination therapy reached statistical significance (p<0.001) versus dutasteride at Month 48. Dutasteride In three two-year, primary efficacy, multicentre, international, placebo-controlled, double-blind studies, 4,325 male subjects with moderate-to-severe BPH symptoms, a prostate volume ≥30 ml, and a PSA value in the range 1.5–10 ng/ml were evaluated on dutasteride 0.5 mg daily or placebo. These studies were then extended in an open-label phase to 4 years for all patients who remained in the study and who received dutasteride at the same 0.5 mg dose. 37% of patients initially randomised to placebo and 40% of patients randomised to dutasteride remained in the study through Year 4. The majority (71%) of the 2,340 subjects in the open-label extension study completed these two additional years of open-label treatment. The most important clinical efficacy endpoints were the AUA-SI (American Urological Association Symptom Index), maximum urinary flow rate (Qmax), and the incidence of acute urinary retention (AUR) and BPH-related surgery. The AUA-SI is a seven-item questionnaire on BPH-related symptoms with a maximum achievable score of 35. The mean baseline score was approximately 17. After six months, one year, and two years, mean improvements of 2.5, 2.5, and 2.3 points were achieved in the placebo group, while mean improvements of 3.2, 3.8, and 4.5 points were achieved in the dutasteride group. The differences between the two groups were statistically significant. The improvement in AUA-SI observed over the first 2 years of the double-blind treatment phase was maintained over the additional two years of the open-label extension study. Qmax (maximum urinary flow rate) The mean baseline Qmax in the studies was approximately 10 ml/s (normal Qmax values are <15 ml/s). After one and two years of treatment, flow rate improved in the placebo group by 0.8 and 0.9 ml/s, respectively, while in the dutasteride group it improved by 1.7 and 2.0 ml/s, respectively. The difference between the groups was statistically significant from Month 1 through Month 24. The increase in maximum urinary flow rate observed over the first 2 years of the double-blind portion of the study was maintained over the additional 2 years of the open-label extension studies. Acute urinary retention and surgical intervention After two years of treatment, the incidence of AUR was 4.2% in the placebo group versus 1.8% in the dutasteride group (57% risk reduction). This difference is statistically significant and means that 42 patients must be treated for two years (95% CI 30–73) to prevent one case of AUR. The incidence of BPH-related surgery after two years of treatment was 4.1% in the placebo group and 2.2% in the dutasteride group (48% risk reduction). This difference is statistically significant and means that 51 patients must be treated for two years (95% CI 33–109) to prevent one surgical intervention. Effect on hair growth The effect of dutasteride on hair growth was not formally studied in Phase III clinical trials; however, 5-α-reductase inhibitors could reduce hair loss and promote hair growth in subjects with androgenic alopecia. Thyroid function Thyroid function was assessed in a one-year study in healthy men. Free thyroxine levels remained stable during dutasteride administration, but at the end of one year of dutasteride dosing, TSH levels were slightly increased (by 0.4 MCIU/ml) compared with placebo. TSH levels were variable, but median TSH levels (1.4–1.9 MCIU/ml) remained within the normal range (0.5–5/6 MCIU/ml), free thyroxine levels were stable within the normal range and were similar with dutasteride and with placebo, and the changes in TSH were not considered clinically significant. In none of the clinical studies was there any evidence that dutasteride adversely affects thyroid function. Breast neoplasia In two-year clinical studies providing 3,374 patient-years of exposure to dutasteride, and at the time of enrolment into the two-year open-label extension period, 2 cases of breast cancer were reported in men treated with dutasteride and 1 case in a patient receiving placebo. In the 4-year CombAT and REDUCE clinical studies, which provided 17,489 patient-years of exposure to dutasteride and 5,027 patient-years of exposure to the dutasteride/tamsulosin combination, no cases of breast cancer were reported in any treatment group. Two case-control epidemiological studies, one conducted in the USA (n=339 breast cancer cases and n=6,780 controls) and the other based on a UK healthcare database (n=398 breast cancer cases and n=3,930 controls), did not show an increased risk of developing male breast cancer with the use of 5-ARIs (see section 4.4). Results from the first study did not identify a positive association with male breast cancer (relative risk for ≥1 year of use prior to breast cancer diagnosis compared with <1 year of use: 0.70; 95% CI 0.34, 1.45). In the second study, the estimated hazard ratio for breast cancer associated with 5-ARI use compared with non-use was 1.08; 95% CI 0.62; 1.87. A causal relationship between male breast cancer and long-term dutasteride use has not been established. Effect on male fertility The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy volunteers aged 18 to 52 years (n=27 on dutasteride, n=23 on placebo) over 52 weeks of treatment and 24 weeks of post-treatment follow-up. After 52 weeks, the mean percentage decreases from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group compared with changes from baseline in the placebo group. Sperm concentration and morphology were not affected. After 24 weeks of post-treatment follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% below baseline. While mean values for all parameters at all time points remained within the normal range and did not meet the predefined criterion for a clinically significant change (30%), two patients in the dutasteride group had sperm counts reduced by more than 90% from their baseline values after 52 weeks of treatment, with partial recovery at the Week 24 follow-up. A reduction in male fertility cannot be excluded. Cardiovascular adverse events In a four-year study evaluating dutasteride in combination with tamsulosin in 4,844 men with BPH (the CombAT study), the incidence of the composite term heart failure was higher in the combination therapy group (14/1,610; 0.9%) than in either monotherapy group: dutasteride (4/1,623; 0.2%) and tamsulosin (10/1,611; 0.6%). In a separate four-year study evaluating 8,231 men aged 50 to 75 years with a previous negative biopsy for prostate cancer and a baseline PSA value between 2.5 ng/ml and 10.0 ng/ml in men aged 50 to 60 years, or 3 ng/ml to 10.0 ng/ml in men over 60 years (the REDUCE study), there was a higher incidence of the composite term heart failure in subjects taking dutasteride 0.5 mg once daily (30/4,105; 0.7%) compared with subjects taking placebo (16/4,126; 0.4%). A post-hoc analysis of this study showed a higher incidence of the composite term heart failure in subjects taking dutasteride together with an alpha1-adrenoceptor antagonist (12/1,152; 1.0%) compared with subjects taking dutasteride without an alpha1-adrenoceptor antagonist (18/2,953; 0.6%), placebo with an alpha1-adrenoceptor antagonist (1/1,399; <0.1%), or placebo without an alpha1-adrenoceptor antagonist (15/2,727; 0.6%). In a meta-analysis of 12 randomised, placebo- or comparator-controlled clinical studies (n=18,802) evaluating the risk of cardiovascular adverse events associated with dutasteride use (compared with controls), no consistent, statistically significant increase was found in the risk of heart failure (RR 1.05; 95% CI 0.71; 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77; 1.30), or stroke (RR 1.20; 95% CI 0.88; 1.64). Prostate cancer and high-grade tumours In the four-year comparison of placebo and dutasteride in 8,231 men aged 50 to 75 years with a previous negative biopsy for prostate cancer and a baseline PSA value between 2.5 ng/ml and 10.0 ng/ml in men aged 50 to 60 years, or 3 ng/ml to 10 ng/ml in men over 60 years (the REDUCE study), needle biopsy data (primarily protocol-required) were available in 6,706 subjects for analysis to determine the Gleason score. In this study, 1,517 subjects were diagnosed with prostate cancer. The majority of biopsy-detected prostate cancers in both treatment groups were diagnosed as low-grade (Gleason score 5–6, 70%). In the dutasteride group (n=29; 0.9%), the incidence of prostate cancers with a Gleason score of 8–10 was higher compared with the placebo group (n=19; 0.6%) (p=0.15). In Years 1 and 2, the number of subjects with cancer of Gleason score 8–10 was similar in the dutasteride group (n=17; 0.5%) and the placebo group (n=18; 0.5%). In Years 3 and 4, more cancers with Gleason score 8–10 were diagnosed in the dutasteride group (n=12; 0.5%) compared with the placebo group (n=1; <0.1%) (p=0.0035). No data are available regarding the effect of dutasteride on prostate cancer risk in men beyond 4 years. The proportion of subjects diagnosed with prostate cancer of Gleason score 8–10 was consistent across the study periods (Years 1–2 and Years 3–4) in the dutasteride group (0.5% in each treatment period), while in the placebo group the proportion of subjects diagnosed with prostate cancer of Gleason score 8–10 was lower during Years 3–4 compared with Years 1–2 (<0.1% vs. 0.5%) (see section 4.4). There was no difference in the incidence of cancers with Gleason score 7–10 (p=0.81). In a two-year follow-up study supplementing the REDUCE study, no new cases of prostate cancer with Gleason score 8–10 were identified. In the 4-year benign prostatic hyperplasia study (CombAT), in which biopsy was not protocol-required and all prostate cancer diagnoses were based on for-cause biopsies, the incidence of prostate cancer with Gleason score 8–10 was (n=8; 0.5%) with dutasteride, (n=11; 0.7%) with tamsulosin, and (n=5; 0.3%) with combination treatment. Four different epidemiological population-based studies (two of which were based on a total population of 174,895, one on a population of 13,892, and one on a population of 38,058) showed that the use of 5-alpha-reductase inhibitors is not associated with the incidence of high-grade prostate cancer, nor with prostate cancer-related mortality or overall mortality. The relationship between dutasteride and high-grade prostate cancer is not yet clarified. Effect on sexual function The effect of dutasteride/tamsulosin on sexual function was evaluated in a double-blind, placebo-controlled study in sexually active men with BPH (n=243 dutasteride/tamsulosin, n=246 placebo). A statistically significant (p<0.001) greater decrease (worsening) in the Men's Sexual Health Questionnaire (MSHQ) was observed over 12 months in the combination therapy group. The decrease was primarily related to worsening in ejaculation and overall satisfaction rather than erectile concerns. These effects did not affect the perception of the dutasteride/tamsulosin combination among study participants; they were rated as having statistically significantly greater satisfaction over 12 months compared with placebo (p<0.05). In this study, sexual adverse events occurred during the 12 months of treatment, and approximately half of them resolved within 6 months after discontinuation of treatment. The dutasteride/tamsulosin combination and dutasteride monotherapy are known to cause adverse events related to sexual function (see section 4.8). As observed in other clinical studies, including CombAT and REDUCE, the incidence of sexual function-related adverse events progressively decreases with continued treatment. Tamsulosin Tamsulosin increases maximum urinary flow rate. It relieves obstructive symptoms by relaxing the smooth muscle of the prostate and urethra, thereby improving irritative symptoms. It also improves storage symptoms, in which bladder instability plays a significant role. These effects on storage and irritative symptoms persist with long-term treatment, so that the need for surgical intervention or catheterisation is significantly delayed. Alpha1-adrenergic receptor antagonists may lower blood pressure by reducing peripheral resistance. In studies with tamsulosin, no clinically significant reduction in blood pressure has been observed.