Finasteride

1 INDICATIONS AND USAGE Finasteride, is a 5α-reductase inhibitor, indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to (1.1) : Improve symptoms Reduce the risk of acute urinary retention Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. Finasteride tablets administered in combination with the alpha-blocker doxazosin are indicated to reduce the risk of symptomatic progression of BPH (a confirmed ≥4 point increase in American Urological Association (AUA) symptom score) (1.2) . Limitations of Use: Finasteride tablets are not approved for the prevention of prostate cancer (1.3) . 1.1 Monotherapy Finasteride tablets are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: - Improve symptoms - Reduce the risk of acute urinary retention - Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. 1.2 Combination with Alpha-Blocker Finasteride tablets administered in combination with the alpha-blocker doxazosin are 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.

2 DOSAGE AND ADMINISTRATION Finasteride tablets may be administered with or without meals. Finasteride tablets may be administered with or without meals (2) . Monotherapy: One tablet (5 mg) taken once a day (2.1) . Combination with Doxazosin: One tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin (2.2) . 2.1 Monotherapy The recommended dose of finasteride tablets is one tablet (5 mg) taken once a day [see Clinical Studies (14.1) ] . 2.2 Combination with Alpha-Blocker The recommended dose of finasteride tablets is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin [see Clinical Studies (14.2) ].

4 CONTRAINDICATIONS Finasteride tablets are contraindicated in the following: Hypersensitivity to any component of this medication. Pregnancy. Finasteride use is contraindicated in females when they are or may potentially be pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant female who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant female should be apprised of the potential hazard to the male fetus. [See also Warnings and Precautions (5.3) , Use in Specific Populations (8.1) , and How Supplied/Storage and Handling (16) .] In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring. Hypersensitivity to any components of this product (4) . Females who are or may potentially be pregnant (4 , 5.3 , 8.1 , 16) .

5 WARNINGS AND PRECAUTIONS Finasteride reduces serum prostate specific antigen (PSA) levels by approximately 50%. However, any confirmed increase in PSA while on finasteride may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor (5.1) . Finasteride may increase the risk of high-grade prostate cancer (5.2 , 6.1) . Females should not handle crushed or broken finasteride tablets when they are pregnant or may potentially be pregnant due to potential risk to a male fetus (5.3 , 8.1 , 16) . Finasteride is not indicated for use in pediatric patients or females (5.4 , 8.1 , 8.2 , 8.4 , 12.3) . Prior to initiating treatment with finasteride for BPH, consideration should be given to other urological conditions that may cause similar symptoms (5.6) . 5.1 Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical studies, finasteride 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, 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 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 therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with finasteride 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. Finasteride 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. 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 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 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 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 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 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, 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.

7 DRUG INTERACTIONS 7.1 Cytochrome P450-Linked Drug Metabolizing Enzyme System 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. 7.2 Other Concomitant Therapy Although specific interaction studies were not performed, finasteride was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, H 2 antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions.

6 ADVERSE REACTIONS ­The drug-related adverse reactions, reported in ≥1% in patients treated with finasteride and greater than in patients treated with placebo over a 4-year study are: impotence, decreased libido, decreased volume of ejaculate, breast enlargement, breast tenderness and rash (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted 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 observed in clinical practice. 4-Year Placebo-Controlled Study ( A Long-Term Efficacy and Safety Study ) In a long-term efficacy and safety study, 1524 patients treated with finasteride and 1516 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 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 * Combined Years 2 to 4 N = 1524 and 1516, finasteride vs. placebo, respectively 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 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, 3047 men with symptomatic BPH were randomized to receive finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) 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. Table 2: Incidence ≥2% in One or More Treatment Groups Drug-Related Clinical Adverse Experiences in MTOPS Adverse Experience Placebo (N=737) (%) Doxazosin 4 mg or 8 mg* (N=756) (%) Finasteride (N=768) (%) Combination (N=786) (%) * 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. Body as a whole Asthenia Headache 7.1 2.3 15.7 4.1 5.3 2 16.8 2.3 Cardiovascular Hypotension Postural Hypotension 0.7 8 3.4 16.7 1.2 9.1 1.5 17.8 Metabolic and Nutritional Peripheral Edema 0.9 2.6 1.3 3.3 Nervous Dizziness Libido Decreased Somnolence 8.1 5.7 1.5 17.7 7 3.7 7.4 10 1.7 23.2 11.6 3.1 Respiratory Dyspnea Rhinitis 0.7 0.5 2.1 1.3 0.7 1 1.9 2.4 Urogenital Abnormal Ejaculation Gynecomastia Impotence Sexual Function Abnormal 2.3 0.7 12.2 0.9 4.5 1.1 14.4 2 7.2 2.2 18.5 2.5 14.1 1.5 22.6 3.1 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 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. Breast Cancer During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 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 that enrolled 3040 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. 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. 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 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 in these events is unknown. - male infertility and/or poor seminal quality were reported rarely in men taking finasteride for the treatment of BPH. Normalization or improvement of poor seminal quality has been reported after discontinuation of finasteride. The independent role of finasteride 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

8.1 Pregnancy Risk Summary Finasteride is contraindicated in pregnant females and not indicated for use in females. Based on animal studies and the mechanism of action, finasteride may cause abnormal development of external genitalia in a male fetus if administered to a pregnant female [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.1) ]. In an embryo-fetal development study in rats, there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring of pregnant rats administered oral finasteride during the period of major organogenesis at doses 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). Decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development were also observed in male offspring at oral maternal doses approximately 0.03 times the MRHD (based 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 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. 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 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 mcg) 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 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 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 mcg) 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.