transurethral resection of the prostate (turp) and prostatectomy. 1.2 combination with alpha-blocker finasteride tablets administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of bph (a confirmed ≥ 4 point increase in american urological association (aua) symptom score). 1.3 limitations of use finasteride tablets are not approved for the prevention of prostate cancer.

ction in clinical studies, finasteride tablets reduced serum psa concentration by approximately 50% within six months of treatment. this decrease is predictable over the entire range of psa values in patients with symptomatic bph, although it may vary in individuals. for interpretation of serial psas in men taking finasteride tablets, a new psa baseline should be established at least six months after starting treatment and psa monitored periodically thereafter. any confirmed increase from the lowest psa value while on finasteride tablets may signal the presence of prostate cancer and should be evaluated, even if psa levels are still within the normal range for men not taking a 5α-reductase inhibitor. non-compliance with finasteride tablets therapy may also affect psa test results. to interpret an isolated psa value in patients treated with finasteride tablets for six months or more, psa values should be doubled for comparison with normal ranges in untreated men. these adjustments preserve the utility of psa to detect prostate cancer in men treated with finasteride tablets. finasteride tablets may also cause decreases in serum psa in the presence of prostate cancer. the ratio of free to total psa (percent free psa) remains constant even under the influence of finasteride tablets. 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. 5.2 increased risk of high-grade prostate cancer men aged 55 and over with a normal digital rectal examination and psa ≤3.0 ng/ml at baseline taking finasteride 5 mg/day in the 7-year prostate cancer prevention trial (pcpt) had an increased risk of gleason score 8 to 10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [ see indications and usage (1.3) and adverse reactions (6.1) . ] similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, avodart) (1% dutasteride vs 0.5% placebo). 5α-reductase inhibitors may increase the risk of development of high-grade prostate cancer. whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established. 5.3 exposure of females- risk to male fetus finasteride tablets is contraindicated in pregnant females and in females who may potentially be pregnant and not indicated for use in females. based on animal studies and the mechanism of action, finasteride tablets may cause abnormal development of external genitalia in a male fetus if administered to a pregnant female. females who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets. finasteride tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. if a pregnant female comes in contact with crushed or broken finasteride tablets, the contact area should be washed immediately with soap and water. [see contraindications (4), use in specific populations (8.1), clinical pharmacology (12.1 and 12.3), and how supplied/storage and handling (16).] 5.4 pediatric patients and females finasteride tablets is not indicated for use in pediatric patients [ see use in specific populations (8.4) and clinical pharmacology (12.3) ] or females [ see also warnings and precautions (5.3) , use in specific populations (8.1) , clinical pharmacology (12.3) , and how supplied/ storage and handling (16) ]. 5.5 effect on semen characteristics treatment with finasteride tablets 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. 5.6 consideration of other urological conditions prior to initiating treatment with finasteride tablets, consideration should be given to other urological conditions that may cause similar symptoms. in addition, prostate cancer and bph may coexist. 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.

over a period of 4 years. the most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with finasteride tablets 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 1 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. table 1: drug-related adverse experiences year 1 (%) years 2, 3 and 4*(%) finasteride placebo finasteride placebo impotence 8.1 3.7 5.1 5.1 decreased libido 6.4 3.4 2.6 2.6 decreased volume of ejaculate 3.7 0.8 1.5 0.5 ejaculation disorder 0.8 0.1 0.2 0.1 breast enlargement 0.5 0.1 1.8 1.1 breast tenderness 0.4 0.1 0.7 0.3 rash 0.5 0.2 0.5 0.1 *combined years 2 to 4 n = 1,524 and 1,516, finasteride vs placebo, respectively phase iii studies and 5-year open extensions the adverse experience profile in the 1-year, placebo-controlled, phase iii studies, the 5-year open extensions, and a long-term efficacy and safety study were similar. medical therapy of prostatic symptoms (mtops) study in the mtops study, 3,047 men with symptomatic bph were randomized to receive finasteride tablets 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [see clinical studies (14.2) .] the incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the mtops study are listed in table 2. the individual adverse effects which occurred more frequently in the combination group compared to either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see table 2). of these, the incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of this adverse experience reported for the two monotherapies. combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience. four patients in mtops reported the adverse experience breast cancer. three of these patients were on finasteride only and one was on combination therapy. [see long-term data.] the mtops study was not specifically designed to make statistical comparisons between groups for reported adverse experiences. in addition, direct comparisons of safety data between the mtops study and previous studies of the single agents may not be appropriate based upon differences in patient population, dosage or dose regimen, and other procedural and study design elements. adverse experience placebo (n=737) (%) doxazosin 4 mg or 8 mg* (n=756) (%) finasteride (n=768) (%) combination (n=786) (%) table 2: incidence ≥2% in one or more treatment groups drug-related clinical adverse experiences in mtops body as a whole asthenia 7.1 15.7 5.3 16.8 headache 2.3 4.1 2.0 2.3 cardiovascular hypotension 0.7 3.4 1.2 1.5 postural hypotension 8.0 16.7 9.1 17.8 metabolic and nutritional peripheral edema 0.9 2.6 1.3 3.3 nervous dizziness 8.1 17.7 7.4 23.2 libido decreased 5.7 7.0 10.0 11.6 somnolence 1.5 3.7 1.7 3.1 respiratory dyspnea 0.7 2.1 0.7 1.9 rhinitis 0.5 1.3 1.0 2.4 urogenital abnormal ejaculation 2.3 4.5 7.2 14.1 gynecomastia 0.7 1.1 2.2 1.5 impotence 12.2 14.4 18.5 22.6 sexual function abnormal 0.9 2.0 2.5 3.1 * doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). the final tolerated dose (4 mg or 8 mg) was administered at end-week 4. only those patients tolerating at least 4 mg were kept on doxazosin. the majority of patients received the 8-mg dose over the duration of the study. long-term data high-grade prostate cancer the pcpt trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a psa ≤3.0 ng/ml. men received either finasteride 5 mg or placebo daily. patients were evaluated annually with psa and digital rectal exams. biopsies were performed for elevated psa, an abnormal digital rectal exam, or the end of study. the incidence of gleason score 8 to 10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%) [see indications and usage (1.3) and warnings and precautions (5.2) ] . in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, avodart), similar results for gleason score 8 to 10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). no clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride tablets. breast cancer during the 4- to 6-year placebo- and comparator-controlled mtops study that enrolled 3,047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. during the 4-year, placebo-controlled a long-term efficacy and safety study study that enrolled 3,040 men, there were 2 cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. during the 7-year placebo-controlled prostate cancer prevention trial (pcpt) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. the relationship between long-term use of finasteride and male breast neoplasia is currently unknown. sexual function there is no evidence of increased sexual adverse experiences with increased duration of treatment with finasteride tablets. new reports of drug-related sexual adverse experiences decreased with duration of therapy. 6.2 postmarketing experience the following additional adverse events have been reported in postmarketing experience with finasteride tablets. because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: - hypersensitivity reactions, such as pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face) - testicular pain -hematospermia - sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, decreased libido and ejaculation disorders (e.g. reduced ejaculate volume). these events were reported rarely in men taking finasteride tablets for the treatment of bph. most men were older and were taking concomitant medications and/or had co-morbid conditions. the independent role of finasteride tablets in these events is unknown. - male infertility and/or poor seminal quality were reported rarely in men taking finasteride tablets for the treatment of bph. normalization or improvement of poor seminal quality has been reported after discontinuation of finasteride. the independent role of finasteride tablets in these events is unknown. - depression - male breast cancer. the following additional adverse event related to sexual dysfunction that continued after discontinuation of treatment has been reported in postmarketing experience with finasteride at lower doses used to treat male pattern baldness. because the event is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure: - orgasm disorders

on auc at animal dose of 0.03 mg/kg/day), along with decreased anogenital distance in male offspring at oral maternal doses approximately 0.003 times the mrhd (based on auc at animal dose of 0.003 mg/kg/day). finasteride tablet is a type ii 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (dht), a hormone necessary for normal development of male genitalia. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (dht) is inhibited by 5α-reductase inhibitors. these outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. females could be exposed to finasteride through contact with crushed or broken finasteride tablets or semen from a male partner taking finasteride tablets. with regard to finasteride exposure through the skin, finasteride tablets are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. females who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets because of possible exposure of a male fetus. with regard to potential finasteride exposure through semen, three studies have been conducted that measured finasteride concentrations in semen in men receiving finasteride tablets 5 mg/day. in these studies the highest amount of finasteride in semen was estimated to be 50-to 100-fold less than the dose of finasteride (5 μg) that had no effect on circulating dht levels in men [see data and clinical pharmacology (12.3)]. data human data in 2 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 semen of 16 subjects receiving finasteride tablets 5 mg/day ranged from undetectable (<1.0 ng/ml) to 21 ng/ml. using the highest semen level measured and assuming 100% absorption would be up to 105 ng per day, which is 50-to 100-fold less than the dose of finasteride (5 μg) that had no effect on circulating dht levels in men [see clinical pharmacology (12.3)]. animal data in an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). at maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (mrhd) of 5 mg/day (based on auc at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. exposure multiples were estimated using data from nonpregnant rats. days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. at oral maternal doses approximately 0.03 times the mrhd (based on auc at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the mrhd (based on auc at animal dose of 0.003 mg/kg/day). no abnormalities were observed in female offspring at any maternal dose of finasteride. no developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the mrhd (based on auc at animal dose of 80 mg/kg/day). slightly decreased fertility was observed in male offspring after administration of about 3 times the mrhd (based on auc at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. no effects on fertility were seen in female offspring under these conditions. no evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6 to 18) at maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). however, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. the fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/ml or about 143 times the highest estimated exposure of pregnant females to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. in confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. no other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose. 8.2 lactation risk summary finasteride tablets are not indicated for use in females. 8.3 females and males of reproductive potential infertility females finasteride tablets are not indicated for use in females. males treatment with finasteride tablets 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 [see warnings and precautions (5.5)]. there have been postmarketing reports of male infertility and/or poor seminal quality; normalization or improvement of seminal quality has been reported after discontinuation of finasteride [see adverse reactions (6.2)]. 8.4 pediatric use finasteride tablets are not indicated for use in pediatric patients. safety and effectiveness in pediatric patients have not been established. 8.5 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 [see clinical pharmacology (12.3) and clinical studies (14)] . 8.6 hepatic impairment caution should be exercised in the administration of finasteride tablets in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver [see clinical pharmacology (12.3) ] . 8.7 renal impairment no dosage adjustment is necessary in patients with renal impairment [see clinical pharmacology (12.3)] .

mg/kg/day), along with decreased anogenital distance in male offspring at oral maternal doses approximately 0.003 times the mrhd (based on auc at animal dose of 0.003 mg/kg/day). finasteride tablet is a type ii 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (dht), a hormone necessary for normal development of male genitalia. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (dht) is inhibited by 5α-reductase inhibitors. these outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. females could be exposed to finasteride through contact with crushed or broken finasteride tablets or semen from a male partner taking finasteride tablets. with regard to finasteride exposure through the skin, finasteride tablets are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. females who are pregnant or may potentially be pregnant should not handle crushed or broken finasteride tablets because of possible exposure of a male fetus. with regard to potential finasteride exposure through semen, three studies have been conducted that measured finasteride concentrations in semen in men receiving finasteride tablets 5 mg/day. in these studies the highest amount of finasteride in semen was estimated to be 50-to 100-fold less than the dose of finasteride (5 μg) that had no effect on circulating dht levels in men [see data and clinical pharmacology (12.3)]. data human data in 2 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 semen of 16 subjects receiving finasteride tablets 5 mg/day ranged from undetectable (<1.0 ng/ml) to 21 ng/ml. using the highest semen level measured and assuming 100% absorption would be up to 105 ng per day, which is 50-to 100-fold less than the dose of finasteride (5 μg) that had no effect on circulating dht levels in men [see clinical pharmacology (12.3)]. animal data in an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). at maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (mrhd) of 5 mg/day (based on auc at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. exposure multiples were estimated using data from nonpregnant rats. days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. at oral maternal doses approximately 0.03 times the mrhd (based on auc at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the mrhd (based on auc at animal dose of 0.003 mg/kg/day). no abnormalities were observed in female offspring at any maternal dose of finasteride. no developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the mrhd (based on auc at animal dose of 80 mg/kg/day). slightly decreased fertility was observed in male offspring after administration of about 3 times the mrhd (based on auc at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. no effects on fertility were seen in female offspring under these conditions. no evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6 to 18) at maternal oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). however, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. the fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20 to 100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/ml or about 143 times the highest estimated exposure of pregnant females to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. in confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. no other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose.

on of dht is maintained throughout the 24-hour dosing interval and with continued treatment. daily dosing of finasteride tablets at 5 mg/day for up to 4 years has been shown to reduce 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. in a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range. in patients receiving finasteride tablets 5 mg/day, increases of about 10% were observed in luteinizing hormone (lh) and follicle-stimulating hormone (fsh), but levels remained within the normal range. in healthy volunteers, treatment with finasteride tablets did not alter the response of lh and fsh to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected. in patients with bph, finasteride tablets have no effect on circulating levels of cortisol, 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. adult males with genetically inherited type ii 5α -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 5α -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 10 times over pretreatment levels, relative to placebo. intraprostatic content of psa was also decreased. in healthy male volunteers treated with finasteride tablets for 14 days, discontinuation of therapy resulted in a return of dht levels to pretreatment levels in 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. 12.3 pharmacokinetics 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 postdose. bioavailability of finasteride was not affected by food. 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 9.4 ng/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 2 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 (<1.0 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- to 100-fold less than the dose of finasteride (5 mcg) that had no effect on circulating dht levels in men [see also use in specific populations (8.1) ] . 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 5α-reductase inhibitory activity of finasteride. 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 of 14 c-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 auc (0-24 hr) after 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). mean (±sd) table 3: mean (sd) pharmacokinetic parameters in healthy young subjects (n=15) bioavailability 63% (34 to 108%) * clearance (ml/min) 165 (55) volume of distribution (l) 76 (14) half-life (hours) 6.2 (2.1) *range pediatric finasteride pharmacokinetics have not been investigated in patients <18 years of age. finasteride is not indicated for use in pediatric patients [ see warnings and precautions (5.4) , use in specific populations (8.4) ]. gender finasteride is not indicated for use in females [ see contraindications (4) , warnings and precautions ( 5.3 and 5.4 ), use in specific populations (8.1) , and how supplied/storage and handling (16) ]. 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 clinical pharmacology (12.3) and use in specific populations (8.5) . ] mean (± sd) 45 to 60 years old (n=12) ≥70 years old (n=12) * first-dose values; all other parameters are last-dose values table 4: mean (sd) noncompartmental pharmacokinetic parameters after multiple doses of 5 mg/day in older men auc (ng•hr/ml) 389 (98) 463 (186) peak concentration (ng/ml) 46.2 (8.7) 48.4 (14.7) time to peak (hours) 1.8 (0.7) 1.8 (0.6) half-life (hours) * 6.0 (1.5) 8.2 (2.5) race the effect of race on finasteride pharmacokinetics has not been studied. hepatic impairment the effect of hepatic impairment on finasteride pharmacokinetics has not been studied. caution should be exercised in the administration of finasteride tablets in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. renal impairment no dosage adjustment is necessary in patients with renal impairment. in patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 ml/min, auc, maximum plasma concentration, half-life, and protein binding after a single dose of 14 c-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.

ange, 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 9.4 ng/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 2 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 (<1.0 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- to 100-fold less than the dose of finasteride (5 mcg) that had no effect on circulating dht levels in men [see also use in specific populations (8.1) ] . 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 5α-reductase inhibitory activity of finasteride. 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 of 14 c-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 auc (0-24 hr) after 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). mean (±sd) table 3: mean (sd) pharmacokinetic parameters in healthy young subjects (n=15) bioavailability 63% (34 to 108%) * clearance (ml/min) 165 (55) volume of distribution (l) 76 (14) half-life (hours) 6.2 (2.1) *range pediatric finasteride pharmacokinetics have not been investigated in patients <18 years of age. finasteride is not indicated for use in pediatric patients [ see warnings and precautions (5.4) , use in specific populations (8.4) ]. gender finasteride is not indicated for use in females [ see contraindications (4) , warnings and precautions ( 5.3 and 5.4 ), use in specific populations (8.1) , and how supplied/storage and handling (16) ]. 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 clinical pharmacology (12.3) and use in specific populations (8.5) . ] mean (± sd) 45 to 60 years old (n=12) ≥70 years old (n=12) * first-dose values; all other parameters are last-dose values table 4: mean (sd) noncompartmental pharmacokinetic parameters after multiple doses of 5 mg/day in older men auc (ng•hr/ml) 389 (98) 463 (186) peak concentration (ng/ml) 46.2 (8.7) 48.4 (14.7) time to peak (hours) 1.8 (0.7) 1.8 (0.6) half-life (hours) * 6.0 (1.5) 8.2 (2.5) race the effect of race on finasteride pharmacokinetics has not been studied. hepatic impairment the effect of hepatic impairment on finasteride pharmacokinetics has not been studied. caution should be exercised in the administration of finasteride tablets in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. renal impairment no dosage adjustment is necessary in patients with renal impairment. in patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 ml/min, auc, maximum plasma concentration, half-life, and protein binding after a single dose of 14 c-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.

the proliferative changes in the leydig cells and an increase in serum lh levels (2- 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 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day). mutagenesis 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. impairment of fertility in sexually mature male rabbits treated with finasteride at 543 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. in sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), 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.

in the leydig cells and an increase in serum lh levels (2- 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 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day). mutagenesis 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. impairment of fertility in sexually mature male rabbits treated with finasteride at 543 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. in sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), 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.

rment 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 tablets 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 1 year in patients treated with finasteride tablets vs placebo (-2.3 vs -1.6), and this improvement continued through year 4. figure 1 symptom 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. effect on acute urinary retention and 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 and acute urinary retention requiring catheterization. complete event information was available for 92% of the patients. the following table (table 5) summarizes the results. patients (%)* event placebo n=1503 finasteride n=1513 relative risk † 95% ci p value † table 5: all treatment failures in a long-term efficacy and safety study all treatment failures 37.1 26.2 0.68 (0.57 to 0.79) <0.001 surgical interventions for bph 10.1 4.6 0.45 (0.32 to 0.63) <0.001 acute urinary retention requiring catheterization 6.6 2.8 0.43 (0.28 to 0.66) < 0.001 two consecutive symptom scores ≥20 9.2 6.7 bladder stone 0.4 0.5 incontinence 2.1 1.7 renal failure 0.5 0.6 uti 5.7 4.9 discontinuation due to worsening of bph, lack of improvement, or to receive other medical treatment 21.8 13.3 * patients with multiple events may be counted more than once for each type of event † hazard ratio based on log rank test compared with placebo, finasteride tablets was associated with a significantly lower risk for acute urinary retention or the need for bph-related surgery [13.2% for placebo vs 6.6% for finasteride tablets; 51% reduction in risk, 95% ci: (34 to 63%)]. compared with placebo, finasteride tablets was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for finasteride tablets; 55% reduction in risk, 95% ci: (37 to 68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for finasteride tablets; 57% reduction in risk, 95% ci: (34 to 72%)]; see figures 2 and 3. figure 2 percent of patients having surgery for bph, including turp figure 3 percent of patients developing acute urinary retention (spontaneous and precipitated) 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 tablets 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 tablets by month 4 (1.0 vs 0.3 ml/sec) which was maintained throughout the study. in the earlier 1-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. 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 tablets who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. finasteride tablets 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 4.) 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 five years of open extension studies. figure 4 prostate volume in a long-term efficacy and safety study 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 4,491 patients with symptomatic bph, demonstrated that, in patients treated with finasteride tablets, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline. finasteride figure 1 finasteride figure 2 finasteride-fig.3_ finasteride figure 4 14.2 combination with alpha-blocker therapy 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 3,047 men with symptomatic bph, who were randomized to receive finasteride tablets 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). all participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. the participant's final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-week 4. the final doxazosin dose was administered once per day, at bedtime. the mean patient age at randomization was 62.6 years (±7.3 years). patients were caucasian (82%), african american (9%), hispanic (7%), asian (1%) or native american (<1%). the mean duration of bph symptoms was 4.7 years (±4.6 years). patients had moderate to severe bph symptoms at baseline with a mean aua symptom score of approximately 17 out of 35 points. mean maximum urinary flow rate was 10.5 ml/sec (±2.6 ml/sec). the mean prostate volume as measured by transrectal ultrasound was 36.3 ml (±20.1 ml). prostate volume was ≤20 ml in 16% of patients, ≥50 ml in 18% of patients and between 21 and 49 ml in 66% of patients. the primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: 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 tablets, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001), respectively. combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with finasteride tablets alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001). (see table 6.) table 6: count and percent incidence of primary outcome events by treatment group in mtops treatment group placebo n=737 doxazosin n=756 finasteride n=768 combination n=786 total n=3,047 event n (%) n (%) n (%) n (%) n (%) aua 4-point rise 100 (13.6) 59 (7.8) 74 (9.6) 41 (5.2) 274 (9.0) acute urinary retention 18 (2.4) 13 (1.7) 6 (0.8) 4 (0.5) 41 (1.3) incontinence 8 (1.1) 11 (1.5) 9 (1.2) 3 (0.4) 31 (1.0) recurrent uti/urosepsis 2 (0.3) 2 (0.3) 0 (0.0) 1 (0.1) 5 (0.2) creatinine rise 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) total events 128 (17.4) 85 (11.2) 89 (11.6) 49 (6.2) 351 (11.5) the majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score, referred to as symptom score progression. the risk of symptom score progression was reduced by 30% (p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with finasteride tablets, doxazosin, or the combination, respectively, compared to patients treated with placebo (see figure 5). combination therapy significantly reduced the risk of symptom score progression compared to the effect of finasteride tablets alone (p<0.001) and compared to doxazosin alone (p=0.037). figure 5 cumulative incidence of a 4-point rise in aua symptom score by treatment group treatment with finasteride tablets, doxazosin or the combination of finasteride tablets with doxazosin, reduced the mean symptom score from baseline at year 4. table 7 provides the mean change from baseline for aua symptom score by treatment group for patients who remained on therapy for four years. table 7: change from baseline in aua symptom score by treatment group at year 4 in mtops placebo n=534 doxazosin n=582 finasteride n=565 combination n=598 baseline mean (sd) 16.8 (6.0) 17.0 (5.9) 17.1 (6.0) 16.8 (5.8) mean change aua symptom score (sd) - 4.9 (5.8) - 6.6 (6.1) - 5.6 (5.9) -7.4 (6.3) comparison to placebo (95% ci) - 1.8 (-2.5, -1.1) - 0.7 (-1.4, 0.0) -2.5 (-3.2, -1.8) comparison to doxazosin alone (95% ci) -0.7 (-1.4, 0.0) comparison to finasteride alone (95% ci) -1.8 (-2.5, -1.1) the results of mtops are consistent with the findings of the 4-year, placebo-controlled study a long-term efficacy and safety study [see clinical studies (14.1) ] in that treatment with finasteride tablets reduces the risk of acute urinary retention and the need for bph-related surgery. in mtops, the risk of developing acute urinary retention was reduced by 67% in patients treated with finasteride tablets compared to patients treated with placebo (0.8% for finasteride tablets and 2.4% for placebo). also, the risk of requiring bph-related invasive therapy was reduced by 64% in patients treated with finasteride tablets compared to patients treated with placebo (2.0% for finasteride tablets and 5.4% for placebo). finasteride-fig.2 14.3 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 tablets arrests the disease process of bph in men with an enlarged prostate.

ablets have not been broken or crushed. if a female who is pregnant or may potentially be pregnant comes in contact with crushed or broken finasteride tablets, the contact area should be washed immediately with soap and water [see contraindications (4) , warnings and precautions (5.3) , use in specific populations (8.1) and how supplied/storage and handling (16)]. 17.3 additional instructions physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with finasteride tablets. this decrease does not appear to interfere with normal sexual function. however, impotence and decreased libido may occur in patients treated with finasteride tablets [see adverse reactions ( 6.1 ) ]. 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 [see adverse reactions ( 6.1 ) ] . physicians should instruct their patients to read the patient package insert before starting therapy with finasteride tablets and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding finasteride tablets. trademarks are the property of their respective owners. manufactured by: alkem laboratories ltd., india. distributed by: ascend laboratories, llc parsippany, nj 07054 revised: january, 2022 pt1819-06