Safety and Tolerability of the Dual 5a-Reductase Inhibitor Dutasteride in thetreatment of Benign Prostatic Hyperplasia

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1 European Urology European Urology 44 (2003) Safety and Tolerability of the Dual 5a-Reductase Inhibitor in thetreatment of Benign Prostatic Hyperplasia Gerald L. Andriole a,*,1, Roger Kirby b a Division of Urologic Surgery, Washington University School of Medicine, 4960 Children s Place, Campus Box 8242, St. Louis, MO 63110, USA b Department of Urology, St. George s Hospital, London, UK Accepted 1 April 2003 Abstract Objective: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5a-reductase inhibitor, dutasteride. Methods: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n ¼ 5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n ¼ 327), and several safety studies conducted in healthy volunteers. Results: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. reduced total serum PSA concentrations by 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an a 1 -blocker, the drug-related adverse event profiles were as would be expected for the individual agents. Conclusions: Considered together, these data demonstrate dutasteride to be well-tolerated. # 2003 Elsevier Science B.V. All rights reserved. Keywords: ; BPH; Safety; Tolerability 1. Introduction a 1 -blockers and 5a-reductase inhibitors (5ARIs) are the mainstay of pharmacotherapy for benign prostatic hyperplasia (BPH). The four widely available a 1 -blockers, tamsulosin, doxazosin, alfuzosin and terazosin, offer comparable therapeutic efficacy both in * Corresponding author. Tel. þ ; Fax: þ address: andrioleg@msnotes.wustl.edu (G.L. Andriole). 1 Disclosure: Professor Andriole is a consultant and investigator for GlaxoSmithKline; funding has been provided by GlaxoSmithKline. terms of symptom relief, as measured using symptomscore questionnaires, and urodynamic improvements, as estimated by peak urinary flow rates [1,2]. The most common adverse events observed with a 1 -blockers are related to their central effects or direct action on the peripheral vasculature, most commonly dizziness (observed in 5 20% of subjects), postural hypotension (2 8%), and also headache, syncope, asthenia and retrograde ejaculation [2,3]. The development of modified release formulations has lead to a reduction in the risk of these adverse events, negating the need for dose titration /03/$ see front matter # 2003 Elsevier Science B.V. All rights reserved. doi: /s (03)

2 G.L. Andriole, R. Kirby / European Urology 44 (2003) A number of randomised clinical trials have demonstrated the clinical efficacy of finasteride, the first clinically available 5ARI, in reducing prostate volume, improving symptom scores and urinary flow rates, and reducing the risk of acute urinary retention (AUR) and BPH-related surgery [4 8]. The most commonly reported adverse events associated with finasteride therapy are sexual dysfunction; typically decreased libido (5%), ejaculatory dysfunction (1%) and impotence (7%), and gynaecomastia (1%) [8]. is a new dual 5ARI for the treatment of BPH. In 2-year placebo-controlled clinical trials, the drug has been demonstrated to reduce prostate volume by approximately 26%, improve symptoms, improve urinary flow, reduce the incidence of acute urinary retention and decrease the likelihood of BPH-related surgery [9,10]. inhibits the 5a-reductase isoenzymes (Type 1 and Type 2) that mediate the synthesis of dihydrotestosterone (DHT), which is the primary androgen responsible for hyperplastic growth in BPH [10]. Finasteride differs from dutasteride in that it inhibits only the Type 2 5a-reductase isoenzyme at therapeutic doses [7]. The dual inhibition of dutasteride leads to nearcomplete suppression of serum DHT (>90%), whereas the inhibition of 5aR2 by finasteride reduces serum DHT by approximately 70% [9,11]. This greater degree of suppression of serum DHT has also been shown to correlate with a high degree of intraprostatic DHT suppression [12]. Theoretically, the greater suppression of DHT arising from dual 5a-reductase inhibition could result in greater efficacy than is observed with selective type 2 inhibition, which could allow escape of DHT from type 1-mediated synthesis. In one 12-month study (GlaxoSmithKline protocol ARI40001), dutasteride compared with finasteride produced numerically, but not statistically significantly, greater improvements in urinary flow rate and symptom scores after 1 year of treatment. The safety and tolerability of dual 5a-reductase inhibition with dutasteride also warrants assessment. Research with finasteride suggests that inhibition of the Type 2 5a-reductase isoenzyme is generally welltolerated and that sexual side effects such as impotence, decreased libido, gynaecomastia, and decreased ejaculate volume are the most common category of drug-related adverse events reported with this class of compounds [7,11,13]. A recently completed programme of large, randomised, controlled clinical trials of dutasteride provides a rich source of data for evaluating the safety and tolerability of this new dual-action 5a-reductase inhibitor. This paper discusses the safety and tolerability profiles of dutasteride as established by these studies, which included large placebo- and finasteride-controlled efficacy and safety trials, a study of combination therapy involving dutasteride and an a 1 -blocker, drug interaction studies, and other healthy volunteer studies. 2. Large placebo- or comparator-controlled studies Data regarding the profile of dutasteride compared with placebo or finasteride for drug-related adverse events, clinical laboratory test results, and prostatespecific antigen (PSA) levels were derived from four large, randomised, double-blind clinical trials. Three of the studies (GlaxoSmithKline protocols ARIA3001, ARIA3002, ARIB3003) were placebo-controlled trials in which patients received either dutasteride 0.5 mg/day or placebo for 2 years, and the fourth study (Glaxo- SmithKline protocol ARI40001) compared dutasteride 0.5 mg/day with finasteride 5 mg/day for 1 year. Data from the three placebo-controlled trials were pooled for analysis, and data from the comparator trial with finasteride were considered alone. Data were included for all patients who took at least one dose of study medication. Analysis of differences between study groups in the incidence of adverse events were conducting using Fisher s Exact Test for the categorical variables and Wilcoxon rank-sum test for the continuous variables Extent of exposure In the three placebo-controlled studies, 4325 patients were randomised to treatment, 2167 of whom received dutasteride and 2158 of whom received placebo (Table 1). The mean duration of exposure to study medication was 604 days (S:D: ¼ 233 days) in the dutasteride group and 598 days (S:D: ¼ 228 days) in the placebo group. Sixty-seven per cent and 70% of patients in the placebo and dutasteride groups respectively completed the two-year study. In the comparator study with finasteride, 1630 patients were randomised to treatment, 813 of whom received dutasteride and 817 of whom received finasteride (Table 1). The mean duration of exposure to study medication was 323 days in the dutasteride group and 329 days in the finasteride group. Ninety per cent and 88% of the patients in the finasteride and dutasteride groups respectively completed the 48 week study Drug-related adverse events In the placebo-controlled studies, most adverse reactions were mild to moderate and generally resolved while on treatment in both the dutasteride and placebo

3 84 G.L. Andriole, R. Kirby / European Urology 44 (2003) Table 1 Demographic and clinical characteristics of patients in large, controlled clinical trials of dutasteride Table 2 Percentage of patients reporting the most common drug-related adverse events in placebo-controlled clinical trials of dutasteride Placebo-controlled studies Event Month (n ¼ 2167) Placebo (n ¼ 2158) Mean age, y (S.D.) 6.5 (7.6) 6.1 (7.4) Ethnic origin, n (%) White 1975 (91) 1986 (92) Black 82 (4) 79 (4) Hispanic 68 (3) 60 (3) Asian/Oriental 28 (1) 20 (<1) Other 14 (<1) 13 (<1) Mean duration of BPH 5.3 (5.0) 5.1 (4.6) symptoms, y (S.D.) Mean time since BPH diagnosis, y (S.D.) 3.7 (4.6) 3.6 (4.4) Comparator-controlled study (n ¼ 813) Finasteride (n ¼ 817) Mean age, y (S.D.) 66.8 (7.2) 66.9 (7.4) Ethnic origin, n (%) White 729 (90) 719 (88) Black 8 (<1) 13 (2) Hispanic 28 (3) 29 (4) Asian/Oriental 32 (4) 35 (4) Other 16 (2) 21 (3) Mean duration of BPH 4.4 (4.0) 4.3 (4.5) symptoms, y (S.D.) Mean time since BPH diagnosis, y (S.D.) 2.7 (3.4) 2.4 (3.2) There were no statistically significant differences in reported baseline parameters between patients in the dutasteride- and placebo-treated groups. groups. Sexual adverse events were the most commonly reported class of drug-related adverse event, occurring more often with dutasteride than with placebo. The vast majority of patients (89% versus 94% for placebo) did not report any drug-related sexual adverse event. The only adverse events that investigators considered to be at least possibly drug-related and that occurred in at least 1% of patients treated with dutasteride or placebo over a 2-year period were impotence, ejaculation disorders, decreased libido and gynaecomastia. The incidence of these adverse events was only slightly higher among dutasteride-treated patients than placebo-treated patients (Table 2). The onset of the majority of possibly drug-related adverse events occurred within the first year of treatment, with a statistically significantly lower incidence of impotence, decreased libido and ejaculatory disorders occurring in the placebo-treated group versus the dutasteridetreated group from months 0 6. Thereafter there were no significant differences between the dutasteride and (n ¼ 2167) (n ¼ 1901) (n ¼ 1725) (n ¼ 1605) Placebo (n ¼ 2158) (n ¼ 1922) (n ¼ 1714) (n ¼ 1555) Impotence 4.7% * 1.4% 1.0% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido 3.0% * 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.0% Ejaculation disorder 1.4% * 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0.0% Gynaecomastia (breast tenderness or enlargement) 0.5% 0.8% * 1.1% * 0.6% * Placebo 0.2% 0.3% 0.3% 0.1% Drug-related adverse events reported in 1% of patients in a group and reported more frequently in the dutasteride group than the placebo group are listed. * p < 0:05, dutasteride versus placebo. placebo groups. The incidence of clinical laboratory abnormalities, including liver function tests, reported as drug-related adverse events was <1% in both the dutasteride group and the placebo group. With the exception of impotence and decreased libido, no other drug-related adverse event was reported in more than 2% of patients or reported more frequently with dutasteride than placebo. These adverse events were no more likely to lead to discontinuation of therapy in the dutasteride group than the placebo group. Impotence resulted in the discontinuation of 24 patients (i.e. 1%) in the dutasteride group (versus 15 patients [<1%] for placebo). Of all drugrelated adverse events in any category, impotence was the most common reason for discontinuation of patients in the dutasteride group. These data are similar to results observed with finasteride [10,11,13]. In the comparator study, the incidence of drug-related adverse events was not significantly different between dutasteride and finasteride (Table 3). The only adverse events that investigators considered to be drug-related and that occurred at an incidence of more than 2% in either group were impotence and decreased libido. Considered together, these adverse-event data show that dutasteride, used daily for up to 2 years, has a tolerability profile comparable with placebo, with the exception of gynaecomastia, impotence and decreased libido, the incidences of which were modestly elevated compared with placebo. Furthermore, the tolerability

4 G.L. Andriole, R. Kirby / European Urology 44 (2003) Table 3 Most common drug-related adverse events [n (% patients)] in a controlled comparator trial of dutasteride and finasteride for BPH (n ¼ 813) Finasteride (n ¼ 817) Impotence 55 (7) 69 (8) Decreased libido 39 (5) 46 (6) Ejaculation disorders 10 (1) 12 (1) Gynaecomastia 9 (1) 9 (1) Headache 11 (1) 9 (1) Dizziness 6 (<1) 11 (1) Malaise/fatigue 12 (1) 12 (1) Adverse events reported in 1% of patients in either group are listed. There were no statistically significant differences between dutasteride- and finasteride-treated patients. profile of dutasteride was comparable with that of finasteride Clinical laboratory data Type 1 5a-reductase, besides being found in the prostate, is concentrated in the liver and skin. Liver function tests, namely serum alkaline phosphatase, alanine aminotransferase and total bilirubin, were included in standard laboratory tests performed at screening and at the end of the first and second years of treatment in the placebo-controlled trials and at screening and at the end of the 1-year treatment period in the comparator trial. Additional clinical chemistry tests (serum glucose, sodium, potassium, albumin, total protein and creatinine) and haematology tests (total white blood cell count, platelet count, haemoglobin, and mean red-blood cell volume) were also performed. In the placebo-controlled studies, the incidence of any laboratory value outside predetermined, standard threshold values did not significantly differ between the dutasteride group and the placebo group during the treatment period (Table 4). The most common postscreening abnormality was an elevation in serum glucose (defined as 1.75 times the upper limit normal), reported by 3% of patients in each treatment group. All other abnormalities occurred in <1% of patients in either the dutasteride or placebo groups. In the comparator study, the incidence of any laboratory values outside predetermined, standard threshold values did not differ between the dutasteride and finasteride groups during the treatment period (Table 4). The incidence of specific abnormalities did not exceed 1% in either treatment group for any parameter. The clinical laboratory data show that dutasteride used daily for up to 2 years does not differ significantly from either placebo or finasteride with respect to effects on clinical laboratory parameters, including results of liver function tests. Table 4 Frequencies [n (% patients)] of most common post-baseline laboratory values outside threshold in large, controlled clinical trials of dutasteride Placebo-controlled trials (n ¼ 2167) Placebo (n ¼ 2158) Any value outside threshold 91 (5) 108 (6) Hepatic function Alkaline phosphatase >1.5 ULN 6 (<1) 11 (<1) Alanine aminotransferase >3.00 ULN 4 (<1) 7 (<1) Haematology Platelet count <0.75 LLN 4 (<1) 10 (<1) Mean cell volume >1.10 ULN 5 (<1) 7 (<1) Haemoglobin <0.75 LLN 3 (<1) 5 (<1) Serum chemistry Glucose <0.70 LLN 3 (<1) 7 (<1) Glucose >1.75 ULN 59 (3) 52 (3) Albumin <0.9 LLN 6 (<1) 10 (<1) Comparator trial (n ¼ 813) Finasteride (n ¼ 817) Any value outside threshold 27 (4) 25 (3) Hepatic function Total bilirubin 2.5 ULN 2 (<1) 0 (0) Alkaline phosphatase >1.5 ULN 5 (<1) 4 (<1) Haematology Platelet count <0.75 LLN 4 (<1) 5 (<1) Mean cell volume <0.90 LLN 6 (<1) 7 (<1) Mean cell volume >1.10 ULN 2 (<1) 2 (<1) Haemoglobin <0.75 LLN 0 (0) 2 (<1) Serum chemistry Glucose <0.70 LLN 1 (<1) 2 (<1) Glucose >1.75 ULN 4 (<1) 4 (<1) LLN: lower limit of normal; ULN: upper limit of normal. There were no statistically significant differences between dutasteride- and placebotreated patients DHT and testosterone levels By inhibiting the conversion of testosterone to DHT, 5a-reductase inhibitors decrease serum DHT levels and increase serum testosterone levels. At the end of 2 years of treatment across the three studies, serum DHT levels were reduced from a comparable baseline by a median of 93.4% among dutasteride-treated patients versus an increase of 4.6% for placebo-treated patients. Serum testosterone levels were increased by a median 19.0% among dutasteride-treated patients but did not change substantially among placebo-treated patients (þ1.4%). Although mean serum testosterone levels increased among dutasteride-treated patients, they remained within normal limits for more than 99% of patients at the end of 2 years of treatment (<5000 pcg/ml; upper limit of normal is 10,000 pcg/ml). The greatest changes in testosterone occurred in men

5 86 G.L. Andriole, R. Kirby / European Urology 44 (2003) that presented with the lowest baseline values. Twelve (<1%) dutasteride-treated patients and 2 (<1%) placebotreated patients had testosterone values slightly higher than 10,000 pcg/ml at the end of 2 years; baseline values for these individuals ranged from 5070 pcg/ml to 9180 pcg/ml Serum PSA levels Results of the placebo-controlled studies show that dutasteride, like finasteride, predictably reduces PSA levels by approximately 50% after 1 or 2 years of treatment, with no effect on the free-to-total PSA ratio. reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6, 12 and 24 months of treatment. This result suggests that, in men initiating 5ARI therapy, a new PSA baseline after 6 months of treatment should be established for assessing potentially cancer-related changes in PSA. Furthermore, in determining whether or not isolated PSA values fall within normal ranges, PSA values should be doubled in patients who have received dutasteride for at least 6 months. With this straightforward adjustment, efforts to screen for prostate cancer need not be compromised in men receiving dutasteride. 3. Combination therapy involving dutasteride and an a 1 -blocker In a combination-therapy study (GlaxoSmithKline protocol 40002), 327 patients with BPH were randomised to receive either combination treatment with once-daily dutasteride (0.5 mg/day) and tamsulosin (0.4 mg/day) for 36 weeks (n ¼ 164; DT36 group) or combination treatment for 24 weeks followed by dutasteride only for 12 weeks (n ¼ 163; DT24 þ D12 group). In this study, as in the placebo-controlled studies, the drug-related adverse events profiles for dutasteride and tamsulosin when used in combination are as would be expected for the individual drugs and there was no evidence of synergistic interaction. Sexual adverse events were the most commonly reported class of drug-related adverse event. The only adverse events that investigators considered to be at least possibly drugrelated and that occurred in at least 5% of patients in either treatment group through the 36-week treatment period were ejaculation disorders, with the majority of these disorders being related to sperm volume (9% DT36 group; 8% DT24 þ D12 group), decreased libido (5% DT36 group; 6% DT24 þ D12 group), impotence (5% DT36 group; 4% DT24 þ D12 group), and malaise/ fatigue (5% DT36 group; 1% DT24 þ D12 group). These data suggest that dutasteride and tamsulosin combination treatment is well-tolerated. 4. Safety studies Besides the combination-therapy study and the placebo- or comparator-controlled trials, studies were conducted in healthy volunteers to investigate the safety profile of dutasteride. Decreases in serum testosterone levels have been speculated to decrease bone mineral density and impact lipid levels [14]. Hence, a study comparing the effects of dutasteride and finasteride on bone mineral density and bone metabolism was conducted. Additionally, several drug-interaction studies were conducted to explore potential pharmacokinetic or pharmacodynamic interactions of dutasteride with commonly used medications Bone density, bone metabolism markers and lipid profiles Decreases in testosterone levels can putatively decrease bone mineral density [14]. This effect is not necessarily expected during administration of 5ARI, which decrease DHT levels and can cause slight increases in testosterone. However, because the possibility exists that bone mineral density can be affected by androgen levels, which are altered during 5ARI therapy, the effect of dutasteride on bone mineral density was assessed in a randomised, double-blind, placebo-controlled study (GlaxoSmithKline protocol ARIA1009), that also included a finasteride arm. The same study also examined the effects of dutasteride on serum lipid profiles. Subjects were randomised to receive 0.5 mg dutasteride, 5.0 mg finasteride or placebo for 52 weeks. Subjects were followed-up for a further 24 weeks following cessation of study medication. Bone density by X-ray absorptiometry was conducted at screening, between weeks and again between weeks of follow-up. Markers for bone resorption and bone formation, namely serum osteocalcin, serum bone alkaline phosphatase and urinary n-telopeptide, were measured at baseline, week 8, 16, 24, and 52, and follow-up weeks 8, 12 and 24. Lipid levels were recorded at baseline, study weeks 8, 24 and 52 and follow-up weeks 4, 8, 12 and 24. Samples were analysed for serum cholesterol, triglycerides, HDL and LDL. There were no clinically significant changes in bone density or bone metabolism markers from baseline, or between treatment groups at weeks or follow-up weeks In addition, there were no clinically significant differences between treatment groups in

6 G.L. Andriole, R. Kirby / European Urology 44 (2003) lipid levels during the study. All treatment groups, including placebo, showed an upward trend in mean cholesterol and LDL during the study. HDL and triglyceride levels fluctuated in all groups throughout the study, but no consistent trends were observed. By week 24 of follow-up, all lipid levels were similar to baseline, with the exception of triglyceride levels in the placebo and dutasteride group, which were increased from baseline (51.4% and 27.8%, respectively). This was not regarded as clinically significant as the increase from baseline in the placebo group was almost twice that of the dutasteride group, and triglycerides were the most variable of the lipid parameters. In conclusion, dutasteride has no clinically significant effect on bone density, bone metabolism markers or lipid profiles. 5. Drug interactions is metabolised by the human cytochrome P-450 isoenzyme CYP3A4. No specific clinical drug interaction studies have been performed to evaluate the impact of CYP3A4 enzyme inhibitors on dutasteride pharmacokinetics. However, across the 3 large placebo-controlled trials with dutasteride, the incidence of adverse events among patients receiving concomitant agents that inhibit CYP3A4 including cimetidine, ciprofloxacin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole and verapamil was similar in both the dutasteride and placebo groups. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, and ciprofloxacin. Single dutasteride doses of 40 mg (i.e. 80 times greater than the recommended therapeutic dose) and repeat doses of 5 mg for 6 months have been given without additional adverse safety outcomes, suggesting a wide therapeutic window for dutasteride. Nevertheless, care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors (e.g. ritonavir). Reduction in dosing frequency can be considered if adverse events are noted. The drug-interaction profile of dutasteride has been assessed in studies with several medications anticipated to be common concomitant therapies. No pharmacodynamic or pharmacokinetic interactions were observed in studies in which healthy male subjects were given (1) the a 1 -blockers tamsulosin (0.4 mg daily) or terazosin (10 mg daily) with dutasteride (40 mg loading dose followed by 0.5 mg daily) for 21 days (Glaxo- SmithKline protocol ARIA1011; n ¼ 48); (2) warfarin (International Normalised Ratio of 1.5 to 2.0) with dutasteride (25 mg loading dose followed by 0.5 mg daily) for 21 days (GlaxoSmithKline protocol ARI10016; n ¼ 24); (3) digoxin (0.25 mg daily) with dutasteride (25 mg loading dose followed by 0.5 mg daily) for 21 days (GlaxoSmithKline protocol ARI10017; n ¼ 24); or (4) cholestyramine (single 12 g dose) 1 hour after administration of dutasteride (single 5 mg dose) (GlaxoSmithKline protocol ARIA1010; n ¼ 24). Finally, in Phase III clinical trials, the adverse event profile of dutasteride among patients receiving concomitant medication did not differ from the profile of those who did not receive concomitant medication. Typically prescribed agents included angiotensinconverting enzyme (ACE) inhibitors, beta blockers, calcium antagonists, diuretics, antihyperlipidemics, corticosteroids, non-steroidal anti-inflammatory drugs, salicylates, phosphodiesterase V inhibitors, and quinolones. 6. Exposure of women to dutasteride 5a-reductase inhibitors decrease circulating DHT, which is important in the ontogenetic development of the urogenital tract in males. Sustained exposure of a pregnant woman to high concentrations of 5a-reductase inhibitors could theoretically result in inadequate development of the genitalia of the male foetus. Such exposure could occur via ingestion of dutasteride or contact with broken gel caps and subsequent absorption through the skin. Because of this potential risk, 5a-reductase inhibitors are contraindicated in women, and pregnant women or women who may become pregnant should not handle dutasteride gel capsules [15]. The risk of exposure of women to dutasteride via contact with semen from a man taking dutasteride has been determined to be minimal. In two primate studies, the potential maximum exposure to a female via 5 ml semen was 186-fold less than the dose that had no effect on male primate embryo foetal development. Likewise, the risk of exposure of women to dutasteride via infusion of blood donated by a male who took dutasteride in the previous 4 to 6 months is minimal. 7. Summary and conclusions The results of clinical studies involving approximately 6000 patients with BPH and hundreds of healthy volunteers demonstrate that the dual 5ARI

7 88 G.L. Andriole, R. Kirby / European Urology 44 (2003) dutasteride is well tolerated during daily use for up to 2 years. In large, well-controlled clinical trials in patients with BPH, dutasteride had a tolerability profile comparable with that of placebo with the exception of a modestly elevated incidence of impotence and decreased libido compared with placebo. The incidence of clinically significant changes in laboratory tests was comparable between dutasteride-treated patients and placebo-treated patients. Administered daily for 1 year, dutasteride did not clinically significantly impact bone metabolism markers, bone mineral density or lipid levels. The safety profile of dutasteride as assessed by drug-related adverse events and clinical laboratory tests did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride is used in combination with an a 1 -blocker, the drug-related adverse event profiles are as would be expected for individual drugs and showed no evidence of synergy. Considered together, these data demonstrate dutasteride to be well-tolerated in long-term use. References [1] Clifford GM, Farmer RDT. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol 2000;38:2 19. [2] Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of a 1 -adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36:1 13. [3] Beduschi MC, Beduschi R, Oesterling JE. Alpha-blockade therapy for benign prostatic hyperplasia: from a nonselective to a more selective a 1 -adrenergic antagonist. Urology 1998;51: [4] Lepor H, Williford W, Barry M, et al. The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. J Urol 1998;160: [5] Tenover JL, Pagano GA, Morton AS, Liss CL, Byrnes CA. Efficacy and tolerability of finasteride in symptomatic benign prostatic hyperplasia: a primary care study, Primary Care Investigator Study Group. Clin Ther 1997;19: [6] Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335: [7] McConnell JD, Bruskewitz R, Walsh PC, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338: [8] Gormley G. The effect of finasteride in men with benign prostatic hyperplasia. J Urol 2002;167: [9] Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5a-reductase inhibition in human benign prostatic hyperplasia. Eur Urol 2000;37: [10] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of dual inhibitor of 5-alpha reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia (BPH). Urology 2002;60:434. [11] Finasteride tablets package insert. Merck and Company, [12] Andriole G, Ray P, Humphrey P, Gleave M, Rittmaster R. The impact of dutasteride, a novel dual 5a-reductase inhibitor on both serum and intraprostatic androgens. Abstract presented at the 18th Congress of the European Association of Urology, Madrid, Spain, March [13] Ekman P. A risk-benefit assessment of treatment with finasteride in benign prostatic hyperplasia. Drug Safety 1998;18: [14] Hafez B. Recent advances in clinical/molecular andrology. Arch Androl 1998;40: [15] tablets approved draft labeling. Application number