Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2020 Publisher: Alphapharm Pty Ltd, Level 1, 30 The Bond, 30 – 34 Hickson Road, Millers Point NSW 2000, www.mylan.com.au
Finasteride, a synthetic 4-azasteroid compound, is a specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme which metabolises testosterone into the more potent androgen dihydrotestosterone (DHT).
In benign prostatic hyperplasia (BPH), enlargement of the prostate gland is dependent upon the conversion of testosterone to DHT within the prostate. Finasteride is highly effective in reducing circulating and intraprostatic DHT. Finasteride has no affinity for the androgen receptor.
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 threefold increase in the risk of acute urinary retention and prostate surgery. Men with enlarged prostates are also three 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 conversion of testosterone to the potent androgen, dihydrotestosterone (DHT) within the prostate. Testosterone, secreted by the testes and adrenal glands, is rapidly converted to DHT by type II 5-alpha-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 5-alpha-reductase. In vitro and in vivo, finasteride has been demonstrated to be a specific type II 5-alpha-reductase inhibitor, and has no affinity for the androgen receptor.
A single dose of finasteride 5 mg produced a rapid reduction in the serum concentration of DHT, with the maximum effect observed after eight hours. While plasma levels of finasteride vary over 24 hours, serum DHT levels remain 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 four 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, serum prostate specific antigen (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 four years. In these studies, circulating levels of testosterone were increased by approximately 10 to 20% yet remained within the physiological range.
When finasteride was given for seven to ten days to patients scheduled for prostatectomy, the drug caused an approximate 80% decrease in intraprostatic DHT. Intraprostatic concentrations of testosterone were increased up to ten times over pretreatment levels.
In healthy volunteers treated with finasteride for 14 days, discontinuation of therapy resulted in a return of DHT values to pretreatment levels within approximately two 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 luteinising hormone (LH) and 9% in follicle stimulating hormone (FSH) was observed in patients treated for 12 months, however, these levels remained well within the physiological 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 finasteride 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 5-alpha-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 5-alpha-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 5-alpha-reductase deficiency.
The data from the studies described below, 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 finasteride reverses the progression of BPH in men with an enlarged prostate.
Finasteride 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two one-year, placebo controlled, randomised, double blind, phase III studies and their five-year open extensions. Of 536 patients originally randomised to receive finasteride 5 mg/day, 234 completed an additional five years of therapy and were available for analysis. The efficacy parameters were symptom score, maximum urinary flow rate, and prostate volume.
Finasteride was further evaluated in the Proscar Long-term Efficacy and Safety Study (PLESS), a double blind, randomised, placebo controlled, four-year, multicentre study. In this study, the effect of therapy with finasteride 5 mg/day on symptoms of BPH and BPH related urological events (surgical intervention (e.g. transurethral resection of the prostate (TURP) and prostatectomy) or acute urinary retention requiring catheterisation) was assessed. 3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and enlarged prostate upon digital examination, were randomised into the study, (1,524 to finasteride, 1,516 to placebo) and 3,016 patients were evaluable for efficacy. 1,883 patients completed the four-year study (1,000 in the finasteride group, 883 in the placebo group). Maximum urinary flow rate and prostate volume were also evaluated.
Investigators collected adverse experience information reported by patients during each visit to the clinic and were asked to assess drug relationship. The drug related adverse experiences seen in PLESS were consistent with those seen in previous studies and are presented in Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS). Although the clinical significance is unclear, a higher incidence of cataracts (4.2% finasteride versus 2.5% placebo) was observed in patients receiving finasteride. None of these cases were considered drug related by the investigator.
In the four-year PLESS study, surgery or acute urinary retention requiring catheterisation occurred in 13.2% of the patients taking placebo compared with 6.6% of the patients taking finasteride, representing a 51% reduction in risk for surgery or acute urinary retention over four years. Finasteride reduced the risk of surgery by 55% (10.1% for placebo versus 4.6% for finasteride) and reduced the risk of acute urinary retention by 57% (6.6% for placebo versus 2.8% for finasteride). The reduction in risk was evident between treatment groups at first evaluation (four months) and was maintained throughout the four-year study. Table 2 shows the rates of occurrence and risk reduction of urological events during the study.
Table 2. Rates of urological events and risk reduction by finasteride 5mg over 4 years:
| Urological events | Placebo (n=1503) %(n) | Finasteride (n=1513) %(n) | Risk reduction |
|---|---|---|---|
| Surgery or acute urinary retention | 13.2 (n=199) | 6.6 (n=100) | 51%* |
| Surgery** | 10.1 (n=152) | 4.6 (n=69) | 55%* |
| TURP | 8.3 (n=125) | 4.2 (n=64) | 49%* |
| Acute urinary retention | 6.6 (n=99) | 2.8 (n=42) | 57%* |
* p <0.001
** BPH-related surgery
In the two one-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 six months was generally necessary to assess whether a beneficial response in symptoms relief had been achieved. The improvement in BPH symptoms was maintained through the first year and throughout an additional five years of extension studies.
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.
In the two one-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 five years of extension studies.
In the four-year PLESS study, there was a clear separation between treatment groups in maximum urinary flow rate in favour of finasteride by month 4, which was maintained throughout the study. Mean maximum urinary flow rate at baseline was approximately 11 mL/second in both treatment groups. In the patients who remained on therapy for the duration of the study and had evaluable urinary flow data, finasteride increased maximum urinary flow rate by 1.9 mL/second compared with 0.2 mL/second in the placebo group.
In the two one-year, phase III studies, mean prostate volume at baseline ranged between 40 to 50 cc. In both studies, prostate volume was significantly reduced compared with baseline and placebo at first evaluation (three months). This effect was maintained through the first year and throughout an additional five years of extension studies.
In the four-year PLESS study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients (n = 284). In patients treated with finasteride, prostate volume was reduced compared with both baseline and placebo throughout the four-year study. Of the patients in the MRI subset who remained on therapy for the duration of the study, finasteride decreased prostate volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at four years) compared with an increase of 14.1% (from 51.3 cc to 58.5 cc) in the placebo group (p <0.001).
A meta-analysis combining one-year data from seven double blind, placebo controlled studies of a similar design, including 4,491 patients with symptomatic BPH, demonstrated that, in patients treated with finasteride, the magnitude of symptoms 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.
Maximum finasteride plasma concentrations are reached approximately two hours after dosing and absorption is complete after six to eight hours. Oral bioavailability of finasteride is approximately 80%. Bioavailability is not affected by food.
Protein binding is approximately 93%. Volume of distribution of finasteride is approximately 76 L. A multiple dose study demonstrated a slow accumulation of small amounts of finasteride over time. After daily dosing of 5 mg/day, trough plasma concentrations of finasteride of about 8 to 10 nanogram/mL were reached and these remained stable over time.
Finasteride has been recovered in the cerebrospinal fluid (CSF) of patients treated with a seven to ten-day course of finasteride, but the drug does not appear to concentrate preferentially in the CSF. Finasteride has also been recovered in the seminal fluid of subjects receiving finasteride 5 mg daily (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). The amount of finasteride in the seminal fluid is 50- to 100-fold less than the dose of finasteride (5 microgram) that had no effect on circulating DHT levels in adult males (see Section 4.6 FERTILITY, PREGNANCY AND LACTATION, DEVELOPMENTAL STUDIES).
Finasteride is metabolised primarily via the cytochrome P450 3A4 enzyme subfamily. Following an oral dose of 14C-finasteride in humans, two metabolites of finasteride were identified which possess not more than 20% of the type II 5-alpha-reductase inhibiting activity of finasteride.
Finasteride displays a mean plasma elimination half-life of six hours. Plasma clearance of finasteride is approximately 165 mL/minute. Following an oral dose of 14C-finasteride, 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 faeces.
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 six hours in men aged 18 to 60 years to eight hours in men aged over 70 years of age. This finding appears to be of no clinical significance and hence a reduction in dosage is not warranted.
In patients with chronic renal impairment, with creatinine clearances ranging from 9 to 55 mL/minute, area under the curve (AUC), maximum plasma concentrations, half-life and protein binding of unchanged finasteride after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in faecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks where exposure of these patients to metabolites would presumably be much greater. Therefore, it is not necessary to adjust dosage in patients with renal insufficiency who are not dialysed, as the therapeutic window of finasteride is adequate and as a correlation between creatinine clearance and accumulation could not be demonstrated.
The effect of race on finasteride pharmacokinetics has not been studied.
The effect of hepatic insufficiency on finasteride pharmacokinetics has not been studied.
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, when Chinese hamster ovary cells were treated with high concentrations (450 to 550 micromol) of finasteride, there was a slight increase in chromosome aberrations.
These concentrations correspond to 4,000 to 5,000 times the peak plasma levels in humans given a total dose of 5 mg. Further, the concentrations (450 to 550 micromol) used in the in vitro studies are not achievable in a biological system. In an in vivo chromosome aberration assay in mice, no treatment related increases in chromosome aberration were observed with finasteride at the maximum tolerated dose (250 mg/kg/day).
In a 24-month carcinogenicity study in rats there was an increase in the incidence of thyroid follicular adenomas in male rats receiving finasteride 160 mg/kg/day (statistically significant trend test). This dose produced a systemic exposure in rats 111 times that observed in humans at the recommended dose (based on AUC (0 to 24 hours) values). The effect of finasteride on the thyroid in rats appears to be due to an increased rate of thyroxine clearance and not a direct effect of the drug. These observations seen in the rat are thought not relevant to humans.
In a 19-month carcinogenicity study in mice, a statistically significant (p less than or equal to 0.05) increase in the incidence of testicular Leydig cell adenoma was observed at a dose of 250 mg/kg/day; no adenomas were seen in mice given 2.5 or 25 mg/kg/day.
In mice at a dose of 25 mg/kg/day and in rats at a dose greater than or equal to 40 mg/kg/day, an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cell and the increase in serum luteinising hormone (LH) levels (two- to threefold above control) has been demonstrated in both rodent species treated with high doses of finasteride. This suggests the Leydig cell changes are secondary to elevated serum LH levels and not due to a direct effect of finasteride.
No drug related Leydig cell changes were seen in either rats or dogs treated with finasteride for one year at doses of 20 mg/kg/day and 45 mg/kg/day respectively, or in mice treated for 19 months at a dose of 2.5 mg/kg/day.
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