5.1 Exposure of Women-Risk to Male Fetus

Finasteride tablets is not indicated for use in women. 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 a male fetus. 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 .  [ See  Indications  and  Usage  (1),  Contraindicat ions  (4),  Use  in  Specific  Populations  (8.1),  How  Supplied / Storage  and  Handling  ( 16 )   and  Patient  Counseling  Infor mation  (17.1).]

5.2 Effects on Prostate Specific Antigen (PSA)

In clinical studies with finasteride tablets 1 mg (finasteride, 1 mg) in men 18 to 41 years of age, the mean value of serum prostate specific antigen (PSA) decreased from 0.7 ng/mL at ba seline to 0.5 ng/mL at Month 12. Further, in clinical studies with finasteride tablets 5 mg (fina steride, 5 mg) when used in older men who have benign prostatic hyperplasia (BPH), PSA levels are decreased by approxi mately 50%. Other studies with finasteride tablets 5 mg showed it may al so cau se de crea ses in serum PSA in the pre sen ce of pro state can cer. The se findings should be taken into account for proper interpretation of serum PSA when evaluating men treated with fina steride. Any confirmed increa se f rom 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 5 α-reductase inhibitor. Non-compl iance to therapy with finasteride tablets may also affe ct PSA te st re sult s

5.3 Increased Risk of High-Grade Prostate Cancer with 5a-Reductase Inhibitors

Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day (5 times the dose of finasteride tablets) in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8 to 10 prost ate cancer (finasteride 1.8% vs placebo 1.1%). [See 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.

5.4 Pediatric Patients

Finasteride Tablets is not indicated for use in pediatric patients [see Use in Specific Populations (8.4) ] .

6.1 Clinical Trials Experience

Because clinical trials are condu cted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates obse rved in clinical practice.

Clinical Studies for finasteride tablets 1 mg in the Treatment of Male Pattern Hair Loss

In three controlled clinical trials for finasteride tablets of 12-month duration, 1.4% of patients taking finasteride tablets (n=945) were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related (1.6% for placebo; n=934).

Clinical adverse experiences that were reported as possibly, probably or definitely drug-related in >1% of patients treated with finasteride tablets or placebo are presented in Table 1.

Integrated analysis of clinical adverse experiences showed that during treatment with finasteride tablets, 36 (3.8%) of 945 men had reported one or more of these adverse experiences as compared to 20 (2.1%) of 934 men treated with placebo (p=0.04). Resolution occurred in men who discontinued therapy with finasteride tablets due to these side effects and in most of those who continued therapy. The incidence of each of the above adverse experiences decreased to <0.3% by the fifth year of treatment with finasteride tablets.

In a study of finasteride 1 mg daily in healthy men, a median decrease in ejaculate volume of 0.3 mL (-11%) compared with 0.2 mL (-8%) for placebo was observed after 48 weeks of treatment. Two other studies showed that finasteride at 5 times the dosage of finasteride tablets (5 mg daily) produced significant median decreases of approximately 0 .5 mL (-25%) compared to placebo in ejaculate volume, but this was reversible after discontinuation of treatment.

In the clinical studies with finasteride tablets, the incidences for breast tenderness and enlargement, hypersensitivity reactions, and testicu lar pain in finasteride-treated patients were not different from those in patients treated with placebo.

Controlled Clinical Trials and Long-Term Open Extension Studies for finasteride tablets    5 mg(finasteride 5 mg) and AVODART (dutasteride) in the Treat ment of Benign Prostatic H yperplasia

In the finasteride tablets 5 mg Long-Term Efficacy and Safety Study (PLESS), a 4-year controlled clinical study, 3040 patients between the ages of 45 and 78 with symptomatic BPH and an enlarged prostate were evaluated for safety over a period of 4 years (1524 on finasteride tablets, 5 mg /day and 1516 on placebo). 3.7% (57 patients) treated with finasteride tablets 5 mg and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to se xual function, which are the most frequently reported adverse reactions.

Table 2 presents the only clinical adverse react ions considered possibly, probably or definitely drug related by the investigator, for which the incidence on finasteride tablets 5 mg 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 impoten ce, decreased libido and ejaculation disorder.

*Combined Years 2 to 4

N = 1524 and 1516, finasteride vs placebo, respectively

The adverse experience profiles in the 1-year, pla cebo-controlled, Phase III BPH studies and the 5-year open extensions with finasteride tablets 5 mg and PLESS were similar.

There is no evidence of increased sexual adverse experiences with i ncreased duration of treatment with finasteride tablets 5 mg. New reports of drug-related sexual adverse experiences decreased with duration of therapy.

During the 4- to 6-year placebo- and comparator- controlled Medical Therapy of Prostatic Symptoms (MTOPS) study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride tablets but no cases in men not treated with finasteride tablets. During the 4-year placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-treated men, but no cases were reported in men treated with finasteride tablets.

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 w ith finasteride tablets, and 1 case of breast cancer in men treated with placebo. The relationship between long-t erm use of finasteride and male breast neoplasia is currently unknown.

The PCPT trial was a 7-year randomized, double- blind, placebo-controlled trial that enrolled 18,882 healthy men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received either finasteride tablets 5 mg (finasteride 5 mg) or p lacebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed f or 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%). In a 4-year placebo -controlled clinical trial with another 5 α-reductase inhibitor [AVODART (dutaster ide)], similar results for Gleason score 8 to 10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). The clinical significance of these findings with respect to use of finasteride tablets by men is unknown.

No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride tablets. Finasteride tablets is not approved to reduce the risk of developing prostate cancer.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of finasteride tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establi sh a causal relationship to drug exposure:

Hypersensitivity Reaction: hypersensitivity reactions such as rash, pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face);

Reproductive System: sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, libido disorders, ejaculation disorders, and orgasm disorders; male infertility and/or poor seminal quality (normalization or improvement of seminal quality has been reported after discontinuation of finasteride); testicular pain. [See Adverse Reactions (6.1).]

Neoplasms: male breast cancer;

Breast disorders: breast tenderness and enlargement;

Nervous System/Psychiatric: depression

8.1 Pregnancy

Pregnancy Category X [see Contraindications (4)].

Finasteride tablets is contraindicated for use in women who are or may become pregnant. Finasteride tablets is a Type II 5 α-reductase inhibitor that prevents conversion of testosterone to 5 α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fet uses. 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 fetu s.

Abnormal male genital development is an expected consequence when conversion of testosterone to 5α- dihydrotestosterone (DHT) is inhibited by 5 α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5 α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or b roken finasteride tablets or semen from a male partner taking finasteride tablets. With regard to finasteride exposure th rough the skin, finasteride tablets are coated and will prevent skin contact with finasteride during norm al handling if the tablets have not been crushed or broken. Women who are pregnant or may beco me pregnant should not handle crushed or broken finasteride tablets because of possib le exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken finasteride tablets, the contact area should be washed immediately with soap and water. With regard to potential finasteride e xposure through semen, a study has been conducted in men receiving finasteride tablets 1 mg/day that measured finasteride concentrations in semen

[see Clinical Pharmacology (12.3)].

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 1 to 684 times the recommended human dose (RHD) of 1 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 0.2 times the RHD (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 0.02 times the RHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring exposed to any dose of finasteride in utero.

No developmental abnormalities were observed in the offspring of untreated females mated with finasteride-treated male rats that received approximately 488 times the RHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 20 times the RHD (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 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 930 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 1 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 120,000 times the highest estimated blood levels of finasteride from semen of men taking 1 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.

8.3 Nursing Mothers

Finasteride tablets is not indicated for use in women.

It is not known whether finast eride is excreted in human milk.

8.4 Pediatric Use

Finasteride tablets is not indicated f or use in pediatric patients.

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical efficacy studies with finasteride tablets did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the elderly for finasteride tablets  [ see   Clinical   Phar macology   ( 12.3)].   However the efficacy of finasteride tablets in the elderly has not been established.

8.6 Hepatic Impairment

Caution should be exercised in the administration of finasteride tablets in those patients with liver function abnormalities, as finasteride is me tabolized extensively in the liver  [ see  Clinical  Phar macology  (12.3) ].

8.7 Renal Impairment

No  dosage  adjustment  is  necessary  in   patients  with  renal  impairment   [ see  Clinical  Phar macology  ( 12.3) ].

12.1 Mechanism of Action

Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into DHT. Two disti nct isozymes are found in mice, rats, monkeys, and humans: Type I and II. Each of these isozymes is diff erentially expressed in tissues and developmental stages. In humans, Type I 5 α-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5 α-reductase is responsible for approximately one-third of circulating DHT. The Type II 5 α-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT.

In humans, the mechanism of action of finasteride is based on its preferential inhibition of the Type II isozyme. Using native tissues (scalp and prostate), in vitro binding studies examining the potential of finasteride to inhibit either isozyme revealed a 100-fold selectivity for the human Type II 5 α-reductase over Type I isozyme (IC50=500 and 4.2 nM for Type I and II, respectively). For both isozymes, the inhibition by finasteride is accompanied by reduct ion of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex). Inhibition of Type II 5 α-reductase blocks the peripheral conversion of testosterone to DHT, res ulting in significant decreases in serum and tissue DHT concentrations.

In men with male pattern hair loss (androgenetic alopecia), the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Administration of finasteride decreases scalp and serum DHT concentrations in these men. The relative contributions of these reductions to the treatment effect of finasteride have not been defined. By this mechanism, finasteride appears to interrupt a key factor in the development of androgenetic alopecia in those patients genetically predisposed.

12.2 Pharmacodynamics

Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a 1-mg tablet. Mean cir culating levels of testosterone and estradiol were increased by approximately 15% as compared to bas eline, but these remained within the physiologic range.

Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. In studies with finasteride, no clinically meaningful changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH) or prolactin were detected. In healthy volunteers, treatment with finasteride did not alt er the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected. Finasteride had no effect on circulating levels of cortisol, thyroid-sti mulating hormone, or thyroxine, nor did it affect the plasma lipid profile (e.g., total cholesterol, low-density lipoproteins, h igh-density lipoproteins and triglycerides) or bone mineral density.

12.3 Pharmacokinetics

Absorption

In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26 to 170%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. At steady state following dosing with 1 mg/day (n=12), maximum finasteride plasma concentration averaged 9.2 ng/mL (range, 4.9 to 13.7 ng/mL) and was reached 1 to 2 hours postdose; AUC(0-24 hr) was 53 ng•hr/mL (range, 20 to 154 ng•hr/mL). Bioav ailability of finasteride was not affected by food.

Distribution

Mean steady-state volume of distribution was 76 liters (range, 44 to 96 liters; n=15). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing.

Finasteride has been found to cross the blood-brain barrier.

Semen levels have been measured in 35 men taking finast eride 1 mg/day for 6 weeks. In 60% (21 of 35) of the samples, finasteride levels were undetectab le (<0.2 ng/mL). The mean finasteride level was 0.26 ng/mL and the highest level measured was 1.52 ng /mL. Using the highest semen level measured and assuming 100% absorption from a 5-mL ejaculate per day, human exposure through vaginal absorption would be up to 7.6 ng per day, which is 650-fold less than the dose of finasteride (5 µg) that had no effect on circulating DHT levels in men. [See Use in Specific Populations (8.1 ) .]

Metabolism

Finasteride is extensively metabolized in the live r, 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.

Excre tion

Following intravenous infusion in healthy young subje cts (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70 to 279 mL/min). Mean terminal half-life in plasma was 4.5 hours (range, 3.3 to 13.4 hours; n=12). Following an oral dose of 14C-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 fe ce s.

Mean terminal half-life is approximately 5 to 6 hours in men 18 to 60 years of age and 8 hours in men more than 70 years of age.

*Range

*First-dose values; all other parameters are last-dose values

Renal I mpair ment

No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging f rom 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to those 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 w ith renal impairment (based on a 60% increase in total radioactivity AUC). However, ifnasteride has been tolerated in men with normal renal function receiving up to 80 mg/day for 12 weeks where exposure of these patien ts to metabolites would presumably be much greater.

Hepatic I mpair ment

The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be used in the administration of finasteride tablets in patien ts with liver function abnormalities, as finasteride is metabolized extensively in the liver.

13.1 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 888 and 2192 times those observed in man receiving the recommended human dose of 1 mg/day. All exposure calculations were based on calculated AU C(0-24 hr)for animals and mean AU C(0-24 hr)  for man (0.05 µg•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 w as observed at 1824 times the human exposure (250 mg/kg/day). In mice at 184 times the human exposure, estimated (25 mg/kg/day) and in rats at 312 times the human exposure (>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 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 240 and 2800 times (20 mg/kg/day and 45 mg/kg/day, respectively), or in mice treated for 19 months at 18.4 times the human exposure, estimated (2.5 mg/kg/day).

No evidence of mutagenicity was observed in an in vi tro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vi tro alkaline elution assay. In an in vi tro chromosome aberration assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tol erated dose of 250 mg/kg/day (1824 times the human exposure) as determined in the carcinogenicity studies. In sexually mature male rabbits treated with finasteride at 4344 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 488 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 p rostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-rel ated effect on testes or on mating performance has been seen in rats or rabbits. This de crease 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 but is not relevant in man.