Finasteride (Tablet, Film Coated)

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The recommended dose is 5 mg orally once a day. Finasteride tablets can be administered alone . Finasteride tablets may be administered with or without meals. No dosage adjustment is necessary for patients with renal impairment or for the elderly .

The development and enlargement of the prostate gland is dependent on the potent androgen, 5��-dihydrotestosterone (DHT). Type II 5��-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs. Finasteride is a competitive and specific inhibitor of Type II 5��-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t~ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5��-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. In man, a single 5 mg oral dose of finasteride produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24 hour dosing interval and with continued treatment. Daily dosing of finasteride at 5 mg/day for up to 4 years has been shown toreduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10 to 20% but remained within the physiologic range. Adult males with genetically inherited Type II 5��-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5��-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH. In patients with BPH treated with finasteride (1 to 100 mg/day) for 7 to 10 days prior to prostatectomy, an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to ten times over pretreatment levels, relative to placebo. Intraprostatic content of prostate-specific antigen (PSA) was also decreased. In healthy male volunteers treated with finasteride for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for 3 months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately 3 months of discontinuation of therapy.<br/>Pharmacokinetics:<br/>Absorption: In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5 mg tablets was 63% (range 34 to 108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27 to 49 ng/mL) and was reached 1 to 2 hours post-dose. Bioavailability of finasteride was not affected by food.<br/>Distribution: Mean steady-state volume of distribution was 76 liters (range, 44 to 96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 and 54% higher than after the first dose in men 45 to 60 years old (n = 12) and���70 years old (n = 12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4 to 9.8 ng/mL) and 8.1 ng/mL (range, 1.8 to 19.7 ng/mL), respectively, in the two age groups. Although steady-state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day was 9.4ng/mL (range, 7.1 to 13.3 ng/mL; n = 22) after over a year of dosing. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. In two studies of healthy subjects (n = 69) receiving finasteride tablets 5 mg/day for 6 to 24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride tablets 5 mg/day ranged from undetectable (<1 ng/mL) to 21 ng/mL. Thus, based on a 5 mL ejaculate volume, the amount of finasteride in semen was estimated to be 50-fold to 100-fold less than the dose of finasteride (5 mcg) that had no effect on circulating DHT levels in men .<br/>Metabolism: Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5��-reductase inhibitory activity of finasteride.<br/>Excretion: In healthy young subjects (n = 15), mean plasma clearance of finasteride was 165 mL/min (range, 70 to 279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3 to 16 hours). Following an oral dose ofC-finasteride in man (n = 6), a mean of 39% (range, 32 to 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51 to 64%) was excreted in the feces. The mean terminal half-life of finasteride in subjects���70 years of age was approximately 8 hours (range, 6 to 15 hours; n = 12), compared with 6 hours (range, 4 to 12 hours; n = 12) in subjects 45 to 60 years of age. As a result, mean AUCafter 17 days of dosing was 15% higher in subjects���70 years of age than in subjects 45 to 60 years of age (p = 0.02).<br/>Special Populations:<br/>Pediatric: Finasteride pharmacokinetics have not been investigated in patients<18 years of age.<br/>Gender: Finasteride pharmacokinetics in women are not available.<br/>Geriatric: No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance. See also CLINICAL PHARMACOLOGY: Pharmacokinetics: Excretion, PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION.<br/>Race: The effect of race on finasteride pharmacokinetics has not been studied.<br/>Renal Insufficiency: No dosage adjustment is necessary in patients with renal insufficiency. In patients with chronic renal impairment, with creatinine clearances ranging from 9 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose ofC-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 fecal 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.<br/>Hepatic Insufficiency: The effect of hepatic insufficiency on finasteride pharmacokinetics has not been studied. Caution should be used in the administration of finasteride in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.<br/>Drug Interactions: No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolism enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin, and no clinically meaningful interactions were found.<br/>Clinical Studies: Finasteride tablet 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, randomized, double-blind studies and their 5 year open extensions. Finasteride was further evaluated in a long-term efficacy and safety study, a double-blind, randomized, placebo-controlled, 4 year, multicenter study. 3,040 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 (1,524 to finasteride, 1,516 to placebo) and 3,016 patients were evaluable for efficacy. 1,883 patients completed the 4 year study (1,000 in the finasteride group, 883 in the placebo group).<br/>Effect on Symptom Score: Symptoms were quantified using a score similar to the American Urological Association Symptom Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one symptom, for a total possible score of 34. Patients in a long-term efficacy and safety study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0 to 34 point scale). Patients randomized to finasteride who remained on therapy for 4 years had a mean (��1 SD) decrease in symptom score of 3.3 (��5.8) points compared with 1.3 (��5.6) points in the placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at one year in patients treated with finasteride vs placebo (-2.3 vs -1.6), and this improvement continued through Year 4. Figure 1Symptom Score in a Long-Term Efficacy and Safety Study Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study. 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 seen during the first year and maintained throughout an additional 5 years of open extension studies.<br/>Effect on the Need for Surgery: In a long-term efficacy and safety study, efficacy was also assessed by evaluating treatment failures. Treatment failure was prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical intervention. Complete event information was available for 92% of the patients. The following table (Table 1) summarizes the results. Compared with placebo, finasteride was associated with a significantly lower risk for the need for BPH-related surgery [13.2% for placebo vs 6.6% for finasteride; 51% reduction in risk, 95% CI: (34 to 63%)]. Compared with placebo, finasteride was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for finasteride; 55% reduction in risk, 95% CI: (37 to 68%)]; see Figure 2. Figure 2Percent of Patients Having Surgery for BPH, Including TURP<br/>Effect on Maximum Urinary Flow Rate: In the patients in a long-term efficacy and safety study 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/sec compared with 0.2 mL/sec in the placebo group. There was a clear difference between treatment groups in maximum urinary flow rate in favor of finasteride by month 4 (1 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier one year studies, increase in maximum urinary flow rate was comparable to a long-term efficacy and safety study and was maintained through the first year and throughout an additional 5 years of open extension studies.<br/>Effect on Prostate Volume: In a long-term efficacy and safety study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients. In patients treated with finasteride who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4 year study. Finasteride 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). (See Figure 3.) Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study. Mean prostate volume at baseline ranged between 40 to 50 cc. The reduction in prostate volume was seen during the first year and maintained throughout an additional 5 years of open extension studies. Figure 3Prostate Volume in a Long-Term Efficacy and Safety Study<br/>Prostate Volume as a Predictor of Therapeutic Response: A meta-analysis combining one year data from seven double-blind, placebo-controlled studies of similar design, including 4,491 patients with symptomatic BPH, demonstrated that, in patients treated with finasteride, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline.<br/>Summary of Clinical Studies: The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume, suggest that finasteride arrests the disease process of BPH in men with an enlarged prostate.

Finasteride tablets are contraindicated in the following: Hypersensitivity to any component of this medication. Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of Type II 5��-reductase inhibitors to inhibit the conversion of testosterone to DHT, finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.

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General: Prior to initiating therapy with finasteride, appropriate evaluation should be performed to identify other conditions such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic disorders that might mimic BPH. Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy. Caution should be used in the administration of finasteride in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.<br/>Effects on PSA and Prostate Cancer Detection: No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride. Patients with BPH and elevated PSA were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these BPH studies, finasteride did not appear to alter the rate of prostate cancer detection, and the overall incidence of prostate cancer was not significantly different in patients treated with finasteride or placebo. Finasteride causes a decrease in serum PSA levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3,000 patients in a long-term efficacy and safety study confirmed that in typical patients treated with finasteride for 6 months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer. Any sustained increases in PSA levels while on finasteride should be carefully evaluated, including consideration of noncompliance to therapy with finasteride. Percent free PSA (free to total PSA ratio) is not significantly decreased by finasteride. The ratio of free to total PSA remains constant even under the influence of finasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value appears necessary.<br/>Information for Patients: Women should not handle crushed or broken finasteride tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to the male fetus . Physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with finasteride. This decrease does not appear to interfere with normal sexual function. However, impotence and decreased libido may occur in patients treated with finasteride . Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been reported . Physicians should instruct their patients to read the patient package insert before starting therapy with finasteride and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding finasteride.<br/>Drug/Laboratory Test Interactions: In patients with BPH, finasteride has no effect 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. Increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in patients receiving finasteride, but levels remained within the normal range. In healthy volunteers, treatment with finasteride did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-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, mobility, morphology, or pH. A 0.6 mL (22.1%) 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 with an average time to return to baseline of 84 weeks.<br/>Drug Interactions: No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found.<br/>Other Concomitant Therapy: Although specific interaction studies were not performed, finasteride was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid,��-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anticonvulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, Hantagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of a tumorigenic effect was observed in a 24 month study in Sprague-Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUCfor animals and mean AUCfor man (0.4 mcg���hr/mL). In a 19 month carcinogenicity study in CD-1 mice, a statistically significant (p���0.05) increase in the incidence of testicular Leydig cell adenomas was observed at a dose of 250 mg/kg/day (228 times the human exposure). In mice at a dose of 25 mg/kg/day (23 times the human exposure, estimated) and in rats at a dose of���40 mg/kg/day (39 times the human exposure) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2-fold to 3-fold above control) has been demonstrated in both rodent species treated with high doses 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 (30 and 350 times, respectively, the human exposure) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (2.3 times the human exposure, estimated). 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, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These concentrations correspond to 4,000 to 5,000 times the peak plasma levels in man given a total dose of 5 mg. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the human exposure) as determined in the carcinogenicity studies. In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (543 times the human exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 80 mg/kg/day of finasteride (61 times the human exposure), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Finasteride is not indicated for use in women. It is not known whether finasteride is excreted in human milk.<br/>Pediatric Use: Finasteride is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.<br/>Geriatric Use: Of the total number of subjects included in a long-term efficacy and safety study, 1,480 and 105 subjects were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly .

Finasteride

Finasteride is generally well tolerated; adverse reactions usually have been mild and transient.<br/>4 Year Placebo-Controlled Study: In a long-term efficacy and safety study, 1,524 patients treated with finasteride and 1,516 patients treated with placebo were evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with finasteride and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 2 presents the only clinical adverse reactions considered possibly, probably or definitely drug-related by the investigator, for which the incidence on finasteride was���1% and greater than placebo over the 4 years of the study. In years 2 to 4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.<br/>Phase III Studies and 5 Year Open Extensions: The adverse experience profile in the one year, placebo-controlled, Phase III studies, the 5 year open extensions, and a long-term efficacy and safety study were similar.<br/>Long-Term Data: There is no evidence of increased adverse experiences with increased duration of treatment with finasteride. New reports of drug-related sexual adverse experiences decreased with duration of therapy. During the 4 year, placebo-controlled a long-term efficacy and safety study that enrolled 3,040 men, there were two cases of breast cancer in placebo-treated men, but no cases were reported in men treated with finasteride. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. In a 7 year placebo-controlled trial that enrolled 18,882 healthy men, 9,060 had prostate needle biopsy data available for analysis. In the finasteride group, 280 (6.4%) men had prostate cancer with Gleason scores of 7 to 10 detected on needle biopsy vs 237 (5.1%) men in the placebo group. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The clinical significance of these findings is unknown. This information from the literature (Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:213���22) is provided for consideration by physicians when finasteride is used as indicated . Finasteride is not approved to reduce the risk of developing prostate cancer.<br/>Post-Marketing Experience: The following additional adverse effects have been reported in post-marketing experience:

Finasteride tablets are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

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