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In the PROSCAR Long-Term Efficacy and Safety Study (PLESS), the effect of therapy with PROSCAR on BPH-related urologic events (surgical intervention [e.g., transurethal resection of the prostate and prostatectomy] or acute urinary retention requiring catheterization) was assessed over a 4-year period in 3016 patients with moderate to severe symptoms of BPH. In this double-blind, randomized, placebo-controlled multicenter study, treatment with PROSCAR reduced the risk of total urologic events by 51% and was also associated with a marked and sustained regression in prostate volume, and a sustained increase in maximum urinary flow rate and improvement in symptoms.
Pharmacology: Benign prostatic hyperplasia (BPH) occurs in the majority of men over the age of 50 and its prevalence increases with age. Epidemiologic studies suggest that enlargement of the prostate gland is associated with a 3-fold increase in the risk of acute urinary retention and prostate surgery. Men with enlarged prostates are also 3 times more likely to have moderate to severe urinary symptoms or a decrease in urinary flow than men with smaller prostates.
The development and enlargement of the prostate gland and subsequent BPH is dependent upon the potent androgen, dihydrotestosterone (DHT). Testosterone, secreted by the testes and adrenal glands, is rapidly converted to DHT by Type II 5α-reductase predominantly in the prostate gland, liver, and skin where it is then preferentially bound to the cell nucleus in those tissues.
Finasteride is a competitive inhibitor of human Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ~30 days). In vitro and in vivo, finasteride has been demonstrated to be a specific Type II 5α -reductase inhibitor, and has no affinity for the androgen receptor.
A single 5 mg dose of finasteride produced a rapid reduction in the serum concentration of DHT, with the maximum effect observed after 8 hours. While plasma levels of finasteride varied over 24 hours, serum DHT levels remained constant during this period, indicating that plasma concentrations of drug do not directly correlate with the plasma concentrations of DHT.
In patients with BPH, finasteride, given for 4 years at a dose of 5 mg/day, was shown to reduce circulating DHT concentrations by approximately 70% and was associated with a median reduction in prostate volume of approximately 20%. Additionally, PSA was reduced approximately 50% from baseline values, suggesting a reduction in prostate epithelial cell growth. Suppression of DHT levels and regression of the hyperplastic prostate with the associated decrease in PSA levels have been maintained in studies of up to 4 years. In these studies, circulating levels of testosterone were increased by approximately 10-20% yet remained within the physiologic range.
When PROSCAR was given for 7-10 days to patients scheduled for prostatectomy, the drug caused a decrease in intraprostatic DHT of approximately 80%. Intraprostatic concentrations of testosterone were increased up to 10 times over pre-treatment levels.
In healthy volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a return of DHT values to pretreatment levels within approximately 2 weeks. In patients treated for three months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately three months of discontinuation of therapy.
Finasteride had no effect compared to placebo on circulating levels of cortisol, estradiol, prolactin, thyroid-stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density. An increase of approximately 15% in luteinizing hormone (LH) and 9% in follicle-stimulating hormone (FSH) was observed in patients treated for 12 months; however, these levels remained well within the physiologic range. Gonadotropin-releasing hormone (GnRH) stimulated levels of LH and FSH were not altered, indicating that regulatory control of the pituitary-testicular axis was not affected. Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, motility, morphology, or pH. A 0.6 mL median decrease in ejaculate volume, with a concomitant reduction in total sperm per ejaculate, was observed. These parameters remained within the normal range, and were reversible upon discontinuation of therapy.
Finasteride appeared to inhibit both C19 and C21 steroid metabolism and hence appeared to have an inhibitory effect on both hepatic and peripheral Type II 5α-reductase activity. The serum DHT metabolites androstenediol glucuronide and androsterone glucuronide were also significantly reduced. This metabolic pattern is similar to that observed in individuals with a genetic deficiency of Type II 5α-reductase who have markedly decreased levels of DHT and small prostates, and who do not develop BPH. These individuals have urogenital defects at birth and biochemical abnormalities but have no other clinically important disorders as a consequence of Type II 5α-reductase deficiency.
Clinical Studies: The data from the studies described as follows, showing reduced risk of acute urinary retention and surgery, improvement in BPH-related symptoms, increased maximum urinary flow rates, and decreasing prostate volume, suggest that PROSCAR reverses the progression of BPH in men with an enlarged prostate.
PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind, Phase III studies and their 5-year open extensions. Of 536 patients originally randomized to receive PROSCAR 5 mg/day, 234 completed an additional 5 years of therapy and were available for analysis. The efficacy parameters were symptom score, maximum urinary flow rate, and prostate volume.
PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a double-blind, randomized, placebo-controlled, 4-year multicenter study. In this study, the effect of therapy with PROSCAR 5 mg/day on symptoms of BPH and BPH-related urologic events (surgical intervention [e.g., transurethral resection of the prostate and prostatectomy] or acute urinary retention requiring catheterization) was assessed. 3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group). Maximum urinary flow rate and prostate volume were also evaluated.
Effect on Acute Urinary Retention and the Need for Surgery: In the 4-year PLESS study, surgery or acute urinary retention requiring catheterization occurred in 13.2% of the patients taking placebo compared with 6.6% of the patients taking PROSCAR, representing a 51% reduction in risk for surgery or acute urinary retention over 4 years. PROSCAR reduced the risk of surgery by 55% (10.1% for placebo vs. 4.6% for PROSCAR) and reduced the risk of acute urinary retention by 57% (6.6% for placebo vs. 2.8% for PROSCAR). The reduction in risk was evident between treatment groups at first evaluation (4 months) and was maintained throughout the 4-year study (see Figures 1 and 2). Table 1 as follows shows the rates of occurrence and risk reduction of urologic events during the study. (See Figure 1.)
Click on icon to see table/diagram/image(See Figure 2.)
Click on icon to see table/diagram/image(See table.)
Click on icon to see table/diagram/imageEffect on Symptom Score: In the two 1-year, Phase III studies, mean total symptom scores decreased from baseline as early as week 2. Compared with placebo, a significant improvement in symptoms was observed by months 7 and 10 in these studies. Although an early improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to assess whether a beneficial response in symptom relief had been achieved. The improvement in BPH symptoms was maintained through the first year and throughout an additional 5 years of extension studies.
Patients in the 4-year PLESS study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0-34 point scale). In the patients who remained on therapy for the duration of the 4-year study, PROSCAR improved the symptom score by 3.3 points compared with 1.3 points in the placebo group (p<0.001). An improvement in symptom score was evident at 1 year in patients treated with PROSCAR, and this improvement continued through year 4. Symptom scores improved in patients treated with placebo in the first year but worsened thereafter. Patients with moderate to severe symptoms at baseline tended to have the greatest improvement in symptom score.
Effect on Maximum Urinary Flow Rate: In the two 1-year, Phase III studies, maximum urinary flow rate was significantly increased compared with baseline by week 2. Compared with placebo, a significant increase in maximum urinary flow rate was observed by months 4 and 7 in these studies. This effect was maintained through the first year and throughout an additional 5 years of extension studies.
In the 4-year PLESS study, there was a clear separation between treatment groups in maximum urinary flow rate in favor of PROSCAR by month 4, which was maintained throughout the study. Mean maximum urinary flow rate at baseline was approximately 11 mL/sec in both treatment groups. In the patients who remained on therapy for the duration of the study and had evaluable urinary flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the placebo group.
Effect on Prostate Volume: In the two 1-year, Phase III studies, mean prostate volume at baseline ranged between 40-50 cc. In both studies, prostate volume was significantly reduced compared with baseline and placebo at first evaluation (3 months). This effect was maintained through the first year and throughout an additional 5 years of extension studies.
In the 4-year PLESS study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients (n=284). In patients treated with PROSCAR, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. Of the patients in the MRI subset who remained on therapy for the duration of the study, PROSCAR decreased prostate volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1% (from 51.3 cc to 58.5 cc) in the placebo group (p<0.001).
Prostate Volume as a Predictor of Therapeutic Response: A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with PROSCAR, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate (approximately 40 cc and greater) at baseline.
Medical Therapy of Prostatic Symptoms: The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized, placebo-controlled, multicenter, 4- to 6- year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day*** (n=756), the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day*** (n=786), or placebo (n=737). The primary endpoint was time from randomization to clinical progression of BPH, defined as the first occurrence of any of the following events: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride, doxazosin, or combination therapy resulted in a significant reduction in the risk of clinical progression of BPH by 34, 39, and 67%, respectively. Combination therapy reduced the risk of clinical progression of BPH to a significantly greater extent than either finasteride or doxazosin alone, which were not significantly different from each other (see Figure 3). The majority of the events (274 out of 351) that constituted BPH progression were confirmed ≥4 point increases in symptom score; the risk of symptom score progression was reduced by 30, 46, and 64% in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Acute urinary retention accounted for 41 of the 351 events of BPH progression; the risk of developing acute urinary retention was reduced by 67, 31, and 79% in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Only the finasteride and combination therapy groups were significantly different from placebo. Small cumulative numbers of events of renal insufficiency, urinary tract infection, and incontinence were reported and were of limited contribution to the primary endpoint of BPH progression. (See Figure 3.)
Click on icon to see table/diagram/imageSecondary outcomes measured in MTOPS included the impact of treatment on BPH-related invasive therapy, symptom score, maximum urinary flow, and prostate volume. The risk of requiring BPH-related invasive therapy was reduced by 64, 3, and 67% in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Only the finasteride and combination therapy groups were significantly different from placebo. All three active treatment groups showed significant improvement in symptom score compared to placebo, and combination therapy was superior to both monotherapy treatments. The effect of combination therapy and doxazosin monotherapy on maximum urinary flow was superior to that of finasteride and placebo. Finasteride and combination treatment decreased prostate volume, whereas, prostate volume increased in men treated with doxazosin or placebo.
The results of MTOPS confirm the findings of the 4-year placebo-controlled study PLESS that treatment with finasteride reduces the risk of acute urinary retention and the need for BPH-related surgery. The results of MTOPS further demonstrate that the combination of finasteride and doxazosin reduces the risk of BPH progression to a significantly greater extent than either therapy administered alone.
Pharmacokinetics: Following an oral dose of 14C-finasteride in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the feces. In this study, two metabolites of finasteride were identified which possess only a small fraction of the 5α-reductase inhibitory activity of finasteride.
Relative to an intravenous reference dose, the oral bioavailability of finasteride is approximately 80%. The bioavailability is not affected by food. Maximum finasteride plasma concentrations are reached approximately two hours after dosing and the absorption is complete after six to eight hours. Finasteride displays a mean plasma elimination half-life of six hours. Protein binding is approximately 93%. Plasma clearance and the volume of distribution of finasteride are approximately 165 mL/min and 76 liters, respectively.
A multiple dose study demonstrated a slow accumulation of small amounts of finasteride over time. After daily dosing of 5 mg/day, steady-state trough plasma concentrations of finasteride are estimated to be 8-10 ng/mL and remained stable over time.
The elimination rate of finasteride is somewhat decreased in the elderly. As subjects advance in age, half-life is prolonged from a mean half-life of approximately 6 hours in men 18-60 years of age to 8 hours in men more than 70 years of age. This finding is of no clinical significance and hence, a reduction in dosage is not warranted.
In patients with chronic renal impairment whose creatinine clearance ranged from 9 to 55 mL/min, the disposition of a single dose of 14C-finasteride was not different from that in healthy volunteers. Protein binding also did not differ in patients with renal impairment. A portion of the metabolites which normally is excreted renally was excreted in the feces. It therefore appears that fecal excretion increases commensurate to the decrease in urinary excretion of metabolites. No adjustment in dosage is necessary in non-dialyzed patients with renal impairment.
Finasteride has been recovered in the cerebrospinal fluid (CSF) of patients treated with a 7-10 day course of finasteride, but the drug does not appear to concentrate preferentially to the CSF. Finasteride has also been recovered in the seminal fluid of subjects receiving 5 mg/day PROSCAR. The amount of finasteride in the seminal fluid was 50- to 100-fold less than the dose of finasteride (5μg) that had no effect on circulating DHT levels in adult males.
