COMPARISON OF DUTASTERIDE (Avodart (marchio registrato) WITH FINASTERIDE (PROSCAR)

SUMMARY

•  No long-term ( > 2 years) clinical trials have directly compared the efficacy and safeaty of dutasteride and finasteride. Withoug such trials, conclusions regarding the relative efficacy and safety of one agent over the other may not be made.

•  Both dutasteride and finasteride are 4-azasteriod competitive inhibitors of 5 alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone (DHT), which is the more potent androgen in the prostate. Dutasteride inhibits both types of isoenzymes (type 1 and 2) of 5 alpha-reductase while finasteride selectivelyinhibits the type 2 isoenzyme. both agents decrease epithelial cell size and funciton within the prostate in patients with benign prostatic hyperplasia (BPH) through an increased rate of apoptosis.

•  In clinical trials, chronic dutasteride thereapy reduces serum DHT by 93 to 94% while finasteride reduces serum DHT by approximately 70%. Reductions in intraprostatic DHT concentrations have not been directly compared between the two drugs. most trials assessing intraprostatic DHT reductions utilized doses higher than those used for the treatment of BPH.

•  In non-comparative trials, chronic therapy with either agent reduced prostate volume significantly in patients with BPH. Both agents have been shown to arrest the disease process in patients with BPH and are indicated to improve symptoms and to reduce the risk of acute urinary retention (AUR) and BPH-related surgery. Both agents increase serum testosterone concentrations by 10 to 20%. Neither drug affects bone mineral density nor serum lipid profiles.

•  The pharmacokinetics of ditasteride are somewhat different than that of finasteride. The major differences include a larger volume of distribution for dutasteide, resulting in a longer elimination half-life. both agents are metabolized by the cytochrome (CYP) P450 3A4 system to active metabolites, although dutasteride is also partly metabolized via the CYP 3A5 pathway, based on in vitro studies. No clinically meaningful drug interactions have been observed with either drug.

•  For both agents, the most frequently reported drug-related adverse events were related to sexual funciton. These included impotence, decreased libido, decreased volume of ejaculation and ejaculation disorders, and breast tenderness and/or enlargement. The onset of drug-related sexual adverse events appears to diminish with time for both drugs.

•  One clinical trial directly comparing dutasteride with finasteride was conducted in Europe. The primary endpoint was to evaluate the effect of either drug on prostate volume after 12 months of double-blind therapy. For the intent-to treat population, prostate volume was reduced from basleine in both the dutasteride and finasteride groups at month 12. dutasteide produced m\numerically but not statistically significant greater improvements in symptoms and urinary flow rates compared with finasteride. Although fewer drug-related sexual adverse events occurred in patients receiving dutasteride than finasteride, there were no significant differneces between the two drugs (17% in the dutasteride group compared with 20% in finasteride-treated patients). Whether similar results would occur with a longer clinical trial ( > 2 years) is not known.

•  A brief 3-month prospective and consecutive study was conducted to evaluate the onset of symptom relief with Avodart (marchio registrato) versus Proscar (finasteride, Merck & Co.) One hundred twenty men with symptomatic benign prostate hyperplasia (BPH) were treated with Avodart (marchio registrato), followed by an additional 120 men treated consecutively with Proscar for 3 months in each trial. Among patients who recieved Avodart (marchio registrato), there were significantly greater reductions in AUA-SO scores compared with Proscar in the first 3 months ( P <0.0016). Conclusion drawn from this study must be considered carefully in light of the study design.

Some information contained in thes rsponse may be outside the approved prescrbing information for Avodart (marchio registrato)?. No long-term clinical trials have compared the efficacy and safety of Avodart (marchio registrato) and Proscar in the U.S. In the absence of such trials, a brief reiew of key areas from the literature and each product's prescribing information is provided for your review and may help differeetiate the products. This response is not intended to ofer recommendations for administering Avodart (marchio registrato) in a manner inconsistnet with its approved labeling. In order for GlaxoSmithKline to monitor the safety of Avodart (marchio registrato), we encourage healthcare professionals to report adverse events or sespected overdoses to the company at 888-825-5249. Please consult the Prescriging Information for Avodart (marchio registrato).

INTRODUCTION

No long-term ( > 2 years) clinical trials have directly compared the efficacy and safety of dutasteride and finasteride. Without such trials, conclusitons regarding the relative efficacy and safety of one agent over the other may not be made. This letter describes differences and similarities between dutasteride and finasteride based on pharacologic, pharmacokinetic and pharmacodynamic effects, as well as a summary of clinical trial information and adverse events reported from these trials. One short-term direct comparative trial conducted in Europe is describedin which patients with benign prostatic hyperplasia (BPH) received either dutasteride or finasteride for 1 year of treatment.

COMPARISON OF PHARMACOLOGY

5alpha-Reductase Isoenzyme Inhibition

Both dutasteide and finasteride are 4-azasteroid inhibitors of 5 a -reductase , the enzyme responsible for converting testosterone to dihydrotestosterone (DHT) in the prostate. DHT is the primary androgen int the prostate and has a major role in the development and progression of benign prostatic hyperplasia (BPH) and other prostate diseases (1,2,3,4) as well as androgenetic alopecia (5,6).

Two isoenzymes of 5 a -reductase exist (type 1 and type 2). Type 2 is the dominant isoenzyme in genital tissues including the prostate, but is also present in the skin and liver. Type 1 5 a -reductase is also found in the skin, liver and prostate, and is the dominant form in sebaceous glands. (1,2,4). Although early studies did not observe the presence of type 1 isoenzyme in the prostate (5), more recent studies using more sensitive assays indicate that both type 1 and type 2 mRNA protein and enzymatic activity are present in prostate tissues. (7,8,9,10,11,12). In one of these studies, mRNA expression for both types 1 and 2 was slightly but significantly increased in BPH tissue when compared to the levels observed in normal prostate tissue. In cancer samples, type 1 mRNA expression was higher than in normal and hyperplastic prostate (11,12) but the level of type 2 mRNA was not statistically different from thatobserved in the normal prostate (11). In th!e liver, type 2 mRNA was expressed at levels similar to those measured in BPH tissue while type 1 mRNA expression was ten times higher. (11)

Finasteride is a competitive inhibitor of 5 a -reductase that selectively inhibits the type 2 isoenzyme, with which it forms a stable enzyme complex. this selective activity is attributed to a much lower affinity for the type 1 isoenzyme, and thus a slow rate of type 1 isoenzyme inhibition. In contrast, dutasteride is a competitive inhibitor of both forms of the enzyme, with 45-fold greater potency than finasteride against type 1 and type 2 isoenzymes at clinically used doses. this dual inhibition may potentially be beneficial in prostatic diseased that depend on androgens, since both isoenzymes are up-regulated in BPH while only the type 1 isoenzyme is up-regulated in prostate cancer, as noted above (2,1). However, whether clinical differences in the treatment of BPH occur between selective versus dual inhibitors of 5 a -reductase is not known.

Turnover from the enzyme complex is extremely slow for both agents. Neither agent possesses anti-gonadotrophic or anit-androgenec properties, and they do not bind to the androgen receptor. (1,14,15).

during the fi4rst several minths of therapy in patients with BPH, both dutrasteride and finasteride cause progressive decreases in epithelial cell size and function within the prostate, through and increased rate of apoptosis, which histologically is manifested by ductal atrophy (1,2,16,17).

Serum DHT Reduction

After chronic administration of doses recommended for the treatment of bPH, serum DHT suppression is significantly greater with dutasteride (0.5 mg daily) than that observed with finasteide (5mg daily). In clinical trials, chronic therapy with dutaseride 0.5mg daily for up to 2 years in patients with BPH resulted in median reductions in serum DHT concentrations of 94% and 93% after 1and 2 years, respectively (14). In contrast, long-term therapy with finasteride 5 mg daily for up to 4 years in patients with BPH suppressed serum DHT concentrations by appr5oximately 70% (15).

Treatment of BPH patients with either agent produces dose-dependent, rapid reductions in serum DHT concentrations (14,15). After 1 and 2 weeks of dutasteride 0.5 mg daily, median serum DHT concentrations were reduced by 85% and 90% respectively (14). With repeated daily dosing, serum DHT concentration reductions are observed within 8 hours after finasteride administration (15).

In addition to the above non-comparative data, a Phase II dose-ranging rial of dutasteride in patients with BPH (n=392) and an enlarged prostate ( > 30 cc as measured by transrectal ultrasound) directly compared various doses of dutasteide with finasteide 5 mg daily in a double-blind, placebo controlled trial. An additional follow-up phase for 4 months after patients had ended the double blind phase was included. The study was not powered to detect clinical differneces in symptoms between dutasteride and finasteride. The mean reduction in baseline DHTconcentration in patients recieving 0.5mg dutasteride daily was greater and less variable than in patients receiveing finasteride 5mg daily (94.7 + 3.3% and 70.8 + 18.3%, respectively, p<0.001). (18)

During the follow-up period (after study medication was stopped), mean DHT concentrations retruned to within 20% of their baseline values at 16 weeks in patients receiving dutasteride, compared with 4 weeks in those receiving finasteride.(18)

Intraprostatic DHT Reduction

Intraprostatic reductions in DHT have been evaluated in Phase II clinical trial in BPH patients after receiving 5mg dutasteride daily, a higher dose than the dosage used for the treatment of BPH. Patients were randomized to receive treatment with dutasteride 5mg daily or placebo for up to 12 weeks prior to transurethral resection of the prostate (TRUP). Mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group. Intraprostatic concentrations were 784 pg/g in the dutasteride group (N=24) compared with 5793 pg/g in the placebo group (n=19, p<0.001). Serum DHT concentration was reduced by a median value of 97.1%. (16)

In another Phase Ii clinical trial, patients weith clinically staged T1, T2 prostate cancer were randomized to receive treatment with high doses of dutasteride or placebo for 6-10 weeks prior to undergoing planned radical prostatectomy. Dutasteride was administered as a loading dose of 10mg daily for the initial 7 days followed by 5mg daily thereafter. Intraprostatic DHT values obtained in patients receiveing dutasteride were 2.9% of those obtained in patients receiving placebo, representing a 97.1% reduction in ccomparison with the placebo group. Serum DHT concentrations were reduced by 96.4% from baseline in patients receibing dutasteride without significantly increasing serum testosterone concentrations. The ratio of serum DHT to testosterone concentrations was also significantly less in subjects receiving dutasteride compared to placebo (>90% reduction with dutasteride compared to baseline). (19)

In a phase Ii trial, 69 patients with BPH were treated with finasteride 1 to 100 mg daily (one-fifth to 200 times the normal daily dosage) for 7-10 days prior to prostatectomy. Intraprostatic DHT concentrations for the entire range of dosed sdministered were approximately 80 lower than those in patients receiving placebo (15,20). Of the 69 patients, 12 patients recieved 5mg daily, the dosage used for the treatment of BPH. In these 12 patients, the exact values for intraprostatic DHT were not described. All dosage levels with in the finasteride griop resulted in statistically significant differences compared to values obtained in the placebo group, but not different from each other. However, the authors stated that the 100mg daily dose was more effective than the 1 and 5mg daily doses. (20) The study firation of 7 days was insufficient time for patients to have achieved steady-state dosing of the frug, since the time to reach steady-state dosing with finasteride is >ulnone 17 days (21).

In another trial, 27 men with symptomatic BPH were treated with placebo, 1mg finasteride daily or 5mg finasteride daily for 6-8 weeks prior to planned transurethral resection of the prostate (TURP). Serum and intraprostatic DHT concentrations correlated well. After 1 and 5mg daily dosing, serum DHT concentrations were reduced by 66% and 70% respectively. Intraprostatic DHT concentrations were reduced by approximately 80% and 90% respectively, in patients receiving 1 and 5 mg daily dosing compared to the mean value obtained at surgery in the placebo group. (22)

In another trial, 27 men with symptomatic BPH were treated with placebo, 1mg finasteride daily or 5mg finasteride daily for 6-8 weeks prior to planned transurethral resection of the prostate (TURP). Serum and intraprostatic DHT concentrations correlated well. After 1 and 5mg daily dosing, serum DHT concentrations were reduced by 66% and 70% respectively. Intraprostatic DHT concentrations were reduced by approximately 80% and 90% respectively, in patients receiving 1 and 5 mg daily dosing compared to the mean value obtained at surgery in the placebo group. (22)

The remaining DHT in the prostate after finasteride therapy is likely to be the result of type 1 5 a -reductase, either originating from the 30% of DHT remaining in the serum of men receiving finasteride or from intraprostatic type 1 5 a -reductase (1). The contribution of remaining DHT in the serum and the small amount of type 1 in the prostate may play a role in maintaining prostatic enlargement (2). Inhibition of both type 1 and type 2 5 a -reductase may potentially offer advantages in the treatment of BPH and other diseases that depend on DHT compared with selective inhibition of the type 2 isoenzyme alone (1,2,3,5). However, long-term direct comparative trials in patients with BPH are necessary to determine whether clinically significant differneces exist among dual and single inhibitors of the enzyme (dutasteride and finasteride, respectively).

The trials discussed above have not evaluated intraprostatic DHT concentration reductions after steady-state dosing had been achieved for either dutasteride or finasteride, and the doses evaluated were significantly higher than those approved for the treatment of BPH in both dutasteride trials and one of the finasteide trials. Intraprostaic concentration reductions achieved with doses approved for the treatment of BPH are not yet available for dutasteride.

Effect on Serum Testorsterone, Bone Density and Lipid Metabolism

Both dutasteride and finasteride increase median circulating testosterone concentration by 10-20% from baseline values, but concentrations remained within normal physiologic limits. In addition, neither agent causes significant changes in bone density or lipid metabolism. (14,15)

Effect on Serum PSA Values

Both agents reduce serum PSA values to similar extents. Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6,12,and 24 months of treatment (14). This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. However, since the ratio of free to total PSA is not significantly altered (23), PSA may still be used as a screening tool for the detection of prostate cancer. To interpret an isolated PSA value in a man treated with either agent for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men.(14,15).

PHARMACOKINETICS AND PHARMACODYNAMICS

The pharmacokinetics of dutasteide have been extensively studied in helthy volunteeres as well as in patients with BPH. (24) The pharmacokinetics of finasteride have been evaluated in healthy volunteers (45-60 years old nd > 70 years old) and patients with renal dysfunction (21). The phormacokinetics of neither drug have been evaluated in patients with hepatic dysfunction.

Major pharmacokinetic and pharmacodynamic parameteres for these drugs are summarized in Table 1. These data are not from direct comparative trials.

Both finasteride and dutasteride are rapidly ablsorbed. Mean bioavailability values are approximately 60%, and administration with food does not significantly affect the bioavailability of either agent. The volume of distribution for both drugs is large, but it is much larger for dutasteride (Table 1). Both drugs are highly bound to plasma proteins. For both drugs, small amounts of the drug are found in the semen but neigher drug accumulates in seminal fluid (14,15,21). the amount of dutasteride partitioning into serum after chronic dosing is 11.5% (14(.

With chronic dosing, both drugs accumulate slowly to steady-state concentrations, althoughserum DHT concentration reductions occur rapidly (14,15). Following daily dosing with dutasteride 0.5mg, 65% and approximately 90% of steady-state serum concentrations are achieved after 1 and 3 months, respectively (14), and steady-state serum concentrations are completely achieved within 6 months (24). The time for steady-state concentrations to be achieved is not known for finasteride, but is longer than 17 days (15,21).

In vitro plasma protein binding studies have been conducted with dutasteride. In these studies, no protein binding displacement occurred with other highly bound drugs such as phenytoin, warfarin or diazepam. (25)

Both finasteride and dutasteride undergo extensive hepatic metabolism primarily via the cytochrome P450 3A4 (CYP 3A4) isoenzyme system (14,15). Dutasteride is also partly metabolized by the CYP 3A5 pathway (26). Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Additionally, dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1000ng/ml, 25 times greater than steady-state serum concentrations in humans (26).

No clinically meaningful drug interactions have been observed with either drug. Both drugs have a wide margin of safety and have been administered in doses of >10 times normal recommended doses for 10 to 12 weeks without an increase in adverse events. (14,20) Dutasteride has been safely administered at doses of 40 mg (80 times greater than the therapeutic 0.5mg dose) daily for 7 days and 5mg (10 times greater than the therapeutic 0.5mg dose) daily for 6 months witohout significant safety concerns (14). Dutasteride in doses up to 5mg daily has been shown to have no effect on the QTc interval (27). Consequently, no dosage adjustment is warranted when dutasteride is given eonccomitantly wit hCYP3A4 inhibitors. (28). Due to the lack of drug interactionstudies, the Prescribing Information includes the following precautionary statemetn "Because of the potentioal for durg-drug interactions, care should be taken when administering dutasteride to patients taking potent!, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir)".

The elimination half-life of dutasteride is 3-5 weeks, much longer than that of finasteride. dollowo\ing discontinuation of dutasteride, serum DHT concentrations retutn to witning 20% of baseline withing 4 months (24). Although the elimination of half-life of finasteide is 6-8 hours, the rate of return to within 20% of baseline DHT concentrations after discontinuation of therapy takes 4 weeks(18) due to the slow rate of turnover of the type 2 isoenzyme-finateride complex, which has a half-life of approximately 30 hours (15,17).

Table 1: Pharmacokinetic Parameters for Dutasteride and Finasteride

CLINICAL EFFICACY 

Finasteride

Finasteride was approved by the FDA for ther treatment of BPH in 1992. Early trials with finasteride that enrolled patients with symptoms of BPH in 1992. Early trials with finasteride that enrolled patients with symptoms of BPH regardless of prstate size demonstrated vfarioable improvements in BPH symptoms (reviewedin reference 29). Boyle et al. (29) subsequently conducted a meta-analysis of 6 previous trials of at least 1 year duration and evaluated the pooled results by smaller and larter prostate size.. Baseline prostate volume was a kdey predictor of outcomes, accounting for approximately 80 of varioationin treatment effects noted between theese studeies. the fiffernences in the magnitude of improbement between finasteride and placebo for symptoms and peak urinary flow rates (Qmax) was significant ofr ment with a baseline PV > 40cc, suggesting that finasteride was benevicialin patients with enlarged prostaes ( > 40cc). (29)

Finasteride was initially evaluated in patients with symptoms of BPH and enlarged prostates cy digital rectal exam (DRE) in two, oney-year placebo ocontrolled double-blind trials each with a 5-year oopen-label extension(15). It was further evaluated in the Proscar Long-term Efficacy and Safety Study (PLESS), the largest trial of finasterideperformed thus far. IN PLESS, a total of 3040 men with symptomatic BPH and an enlarged prostate on DRE were randomized to receive finasteride 5mg daily (n=1524) or placebo (n=1516) for 4 years. Of the 3040 men, 1883 completed the 4-year study (1000 finasteride, 883 placebo). The primary endpoint of the study was the effect of mecication on symptom score as measured by the change from baseline American Urological Association Symptom Index (AUA-SI) score. Prostate volume was measured in a subset of 312 patients from the study (157 in finasteride group and 155 in placebo) and was measured by magnetic resonance imaging (MRI) at yearly inter!vals. (30)

Fnasteride treatment resulted in significant improvement in symptom scores and maximum urinary flow rate (Table 2). The mean prostate volume decreeased furing the first year in the finasteride group, with no further increase thereafter., while it increased continuously in patients recieving placego. At 4 years, the risk of undergoing BpH-related surgery was 55% lowerin patients receiving finasteride compared with placebo, and the risk reduction for experiencing acute urinary retention (AUR) was reduced by 57% (all ;,0.001).(30)

Table 2. Clinical endpoints in PLESS after 48 months of finasteride or placebo (30)

Primary Endpoint

Finasteride

(N=1513)

%

Placebo

(N=1503)

%

Difference

between groups

AUA-SI

Change from baseline

-2.6

-1.0

1.6

SecondaryEndpoints

Finasteride

(N=1513)

%

Placebo

(N=1503)

%

Risk Reduction

%

BPH Surgery or Acute urinary retention

7

13

51

BPH Surgery Transurethral prostatectomy

5

4

10

8

55

49

Acute urinary retention

Spontaneous

Precipitated

3

 

1

2

7

 

4

3

57

 

62

52

Subset Analysis

n=157

n=155

Difference between groups

Prostate Volume Change from baseline

-18%

+14%

32%

Drug-related sexual adverse events, gynecomastia and rash occurred more frequently in the finasteride group than in the placebo group. Most patients experienced the onset of drug-related adverse events within the first year of therapy. (30)

Dutasteride

Three essentially identical randomized, double-blind, placebo-controlled parallel clinical trials evaluated the efficacy and safety of dutasteride 0.5 mg once daily for 2 years for the treatment of BPH followed by a 2-year open-label extension. A pooled analysis of these 3 trials was prospectively planned. The trials were generally similar to those of the PLESS trial with finasteride. The mean baseline AUA-SI symptom scores and prostate volumes were relatively similar among the trials (AUA-SI: 15 and 17 units, prostate volume: 54 and 55cc for finasteride and dutasteride, respectively). However, there were some notable differences in trial design between the studies, which are noted below.

The dutasteride trials included larger number of patients (N=4325) and patients received double-blind therapy for 2 years, as compared with 4 years in PLESS. Only patients with serum PSA values > 1.5ng/mL were enrolled, while the PLESS trial enrolled patient with lower PSA values also. Both trials excluded patients with serum PSA values > 10 ng/mL. Patients were enrolled in the dutasteride trials if their prostate volume was > 30cc and all patients had serial prostate volume measurements by transrectal ultrasound (TRUS). In addition, the primary endpoint in the dutasteride trials at the 24-month timepoint was the incidence of AUR. (24)

Results of the dutasteride clinical trials are presented in Table 3, which represents intent-to-treat analyses using the last observation carried forward. At 2 years, dutasteride reduced the risk of AUR by 57% compared with placebo (p<0.001), and the risk reduction increased with time during the trial (24). The mean prostate volume decreased by 26.7% at 24 months. Reductions in prostate volume were observed at 1 month and continued throughout the 24-month period. In addition, at 2 years, dutasteride therapy reduced the risk of BPH-related surgical interventions by 48% (all p<0.001). Symptom scores improved by 3 months in 1 of the 3 studies and by month 12 in the other 2 studies. (14, 24). Similar results were found when data obtained at the last visit were used, which have recently been published (31).

Table 3. Clinical endpoints in Phase III trials after 24 months of dutasteride or placebo (14)

Outcome

Dutasteride

(N=2167)

Placebo

(N=2158)

Difference between

groups

Primary Endpoint

 

 

Risk Reduction

Acute Urinary Retention

1.8%

4.2%

57%

Secondary Endpoints

 

 

 

BPH-related Surgery

2.2%

4.1%

48%

BPH surgery or Acute Urinary Retention

3.5%

6.8%

49%

 

 

 

Difference between groups

AUA-SI

Change from baseline (points)

-3.8

-1.7

-2.1

Prostate Volume

Change from baseline

-26.7%

-2.2%

-24.5%

Drug-related sexual adverse events, gynecomastia and rash occurred more frequently in the finasteride group than in the placebo group. Most patients experienced the onset of drug-related adverse events within the first year of therapy. (28, 31)

In both the finasteride and dutasteride trials, discontinuation rates were significantly higher in the placebo group as compared to the active treatment groups. (28, 30, 31).

INDICATIONS

Both dutasteride and finasteride arrest the disease process of men with BPH and an enlarged prostate and are indicated to improve symptoms, reduce the risk of AUR, and reduce the need for BPH-related surgery. (14, 15)

ADVERSE EVENTS 

Without direct, comparative clinical trials, it is not possible to determine the comparative incidence of adverse events between finasteride and dutasteride. Differences in reported adverse event rates may reflect differences in patient populations, trial design, or methods of adverse event collection and coding. Please refer to the Prescribing Information for both Proscar and Avodart (marchio registrato) for reports of adverse event experienced with each agent during the clinical trials.

Since finasteride has been available in the U.S. since 1992, longer-term safety data are available with finasteride. Both agents have a wide margin of safety, as demonstrated by the short-term administration of much higher doses than those approved for the treatment of BPH. In clinical trials, doses of up to 80 mg finasteride daily or 5 mg dutasteride daily for 12 weeks have been well-tolerated (14, 15).

For both agents, the most frequently reported drug-related adverse events were related to sexual function. These included impotence, decreased libido, decreased volume of ejaculation and ejaculation disorders, and breast tenderness and /or enlargement. For both agents, the onset of drug-related sexual adverse events appears to diminish with time, and there is no evidence of increased adverse events with increased duration of therapy. (14, 15, 28)

SHORT-TERM COMPARATIVE CLINICAL TRIAL 

EPICS (Enlarged Prostate International Comparator Study) was a randomized double-blind active-controlled trial that compared 12 months of dutasteride and finasteride therapy in 27 European countries.

The study was conducted to fulfill European registration requirements. The primary objective of the study was the change in baseline prostate volume at 1 year. Safety and tolerability data were also obtained. Patients with BPH (N= 1630) were randomized to receive either dutasteride 0.5 mg once daily (n=813) or finasteride 5.0 mg once daily (n=817) for 12 months. Of the patients randomized, 1454 completed the 12-month double-blind phase (719 dutasteride and 735 finasteride). (32)

Patients enrolled were males > 50 years old with BPH according to medical history and physical examination including a DRE, an AUA-SI score > 12, prostate volume > 30cc as determined by transrectal ultrasound, and serum PSA > 1.5 but < 10ng/mL, urinary flow rate < 15 mL/sec, and a minimum voided volume > 125 mL. Patients were excluded if they had a post-void residual volume > 250 mL or a PSA < 1.5ng.mL or > 10ng/mL.

For the intent-to treat population, prostate volume was reduced from baseline in both the dutasteride and finasteride groups at month 12. The difference between the two agents was not statistically significant. Dutasteride produced numerically but not statistically significant greater improvements in symptoms and urinary flow rates compared with finasteride. PSA levels were also decreased from baseline to a similar degree in both treatment groups. (32)

Although fewer drug-related sexual adverse events occurred in patients receiving dutasteride than finasteride, there were no significant differences betwe3en the two drugs (17% in the dutasteride group compared with 20% in finasteride-treated patients). The most frequent drug-related adverse events were sexual in nature and are listed in Table 4.

Table 4. Summary of drug-Related Adverse Events after 1-year of dutasteride or finasteride (32)

 

Dutasteride 0.5 mg daily

N=813

Finasteride 5 mg daily

N=817

Any adverse event

17%

20%

Sexual adverse event % Gynecomastia

11%

14%

Impotence

7%

8%

Decreased libido

5%

6%

Ejaculation disorders

1%

1%

Gynecomastia

1%

1%

Few adverse events led to patient withdrawal from the study (5% of dutasteride patients and 4% of finasteride-treated patients). (32) Thus, dutasteride appeared to be as safe as finasteride for pat9ients with BPH.

Since BPH is a long-term, gradually progressive disease, it is possible that differentiation between the two drugs may not be apparent in a shorter-term trial. It is unknown whether significant differences in clinical outcomes between dutasteride and finasteride would occur with longer treatment duration.

Finally, a brief 3-mnth prospective and consecutive study was conducted to evaluate the onset of symptom relief with Avodart (marchio registrato) versus Proscar (33). One hundred twenty men with symptomatic BPH were treated with Avodart (marchio registrato) , followed by and additional 120 men treated consecutively with Proscar for 3 months in each trial. Patients were instructed not to expect any symptomatic benefit until at least 6 months. The American Urological Association Symptom Index (AUA-SI) was used to assess symptom scores at baseline and following 3 months of therapy with each drug.

No significant differences were noted between patients at baseline in terms of age or serum levels of PSA. Among patients who received Avodart (marchio registrato) there were significantly greater reductions in AUA-SI scores compared with Proscar . Specifically, 68 (57%) of patients experienced no improvement over the 3-month period with Avodart (marchio registrato) compared with 92 (77%) of patients treated with Proscar . One unit improvements in the AUA-SI (36(30%) and 22 (18%)) and 2-unit improvements (14 (12%) and 5 (4%)) were noted in patients treated with Avodart (marchio registrato) and Proscar, respectively. A corresponding 3-unit AUA-SI score reduction was noted in 2 (2%) and 1 (1%) of Avodart (marchio registrato) and Proscar patients, respectively. The estimated difference (with 95% CI; 7.5%, 32.5%; two-sided Fisher's Exact test P < 0.0016). Conclusion drawn from this study must be considered carefully in light of the study design.

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