Finasteride

INDICATIONS & USAGE Finasteride tablets, are 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 USP 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) ( 1.2 ). Limitations of Use: Finasteride tablets USP is not approved for the prevention of prostate cancer ( 1.3 ). (1) 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 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.

DOSAGE AND ADMINISTRATION Finasteride tablets USP, 5 mg may be administered with or without meals. Finasteride 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 USP, 5 mg 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 USP, 5 mg is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin . [see ] Clinical Studies (14.2)

WARNINGS AND PRECAUTIONS • Finasteride tablets reduces serum prostate specific antigen (PSA) levels by approximately 50%. However, any confirmed increase in PSA while on finasteride tablets 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 tablets 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 tablets are 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 tablets 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 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.

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) , How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2) .] 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 ).(4)

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 include 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 doses of 1 mg or more were concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, analgesics, angiotensin-converting enzyme (ACE) inhibitors, anticonvulsants, benzodiazepines, beta blockers, calcium-channel blockers, cardiac nitrates, diuretics, H 2 antagonists, HMG-CoA reductase inhibitors, prostaglandin synthetase inhibitors (also referred to as NSAIDs), and quinolone anti-infectives without evidence of clinically significant adverse interactions.

ADVERSE REACTIONS The most common adverse reactions, reported in ≥1% of patients treated with finasteride and greater than in patients treated with placebo are: decreased libido, erectile dysfunction and ejaculation disorder (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Rising Health, LLC at 1-833-395-6928 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. Clinical Studies for Finasteride 1 mg in the Treatment of Male Pattern Hair Loss In three controlled clinical trials for finasteride of 12-month duration, 1.4% of patients taking finasteride (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 or placebo are presented in Table 1. TABLE 1: Drug-Related Adverse Experiences for Finasteride 1 mg in Year 1 (%) MALE PATTERN HAIR LOSS Finasteride N=945 Placebo N=934 Decreased Libido 1.8 1.3 Erectile Dysfunction 1.3 0.7 Ejaculation Disorder (Decreased Volume of Ejaculate) 1.2 (0.8) 0.7 (0.4) Discontinuation due to drug-related sexual adverse experiences 1.2 0.9 Integrated analysis of clinical adverse experiences showed that during treatment with finasteride, 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 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. 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 (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, the incidences for breast tenderness and enlargement, hypersensitivity reactions, and testicular 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 5 mg and AVODART (dutasteride) in the Treatment of Benign Prostatic Hyperplasia In the finasteride 5 mg long-term efficacy and safety study, 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 5 mg/day and 1516 on placebo). 3.7% (57 patients) treated with finasteride 5 mg and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 2 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on finasteride 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 impotence, decreased libido and ejaculation disorder. TABLE 2: Drug-Related Adverse Experiences for Finasteride 5 mg BENIGN PROSTATIC HYPERPLASIA Year 1 (%) Years 2, 3 and 4* (%) Finasteride 5 mg Placebo Finasteride 5 mg 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 = 1524 and 1516, finasteride vs. placebo, respectively The adverse experience profiles in the 1-year, placebo-controlled, Phase III BPH studies and the 5-year open extensions with finasteride 5 mg and long-term efficacy and safety study were similar. There is no evidence of increased sexual adverse experiences with increased duration of treatment with finasteride 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 5 mg but no cases in men not treated with finasteride 5 mg. During the 4-year placebo-controlled long-term efficacy and safety 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 5 mg. 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 5 mg, 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. 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 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%). In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor [AVODART (dutasteride)], 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 by men is unknown. No clinical benefit has been demonstrated in patients with prostate cancer treated with finasteride 5 mg. Finasteride 5 mg is not approved to reduce the risk of developing prostate cancer. Sexual Function Questionnaire A sexual function questionnaire was self-administered by patients participating in the two vertex baldness trials to detect more subtle changes in sexual function. At Month 12, statistically significant differences in favor of placebo were found in 3 of 4 domains (sexual interest, erections, and perception of sexual problems). However, no significant difference was seen in the question on overall satisfaction with sex life. In one of the two vertex baldness studies, patients were questioned on non-scalp body hair growth. Finasteride did not appear to affect non-scalp body hair. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of finasteride. Because these reactions 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 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 discontinuat

Mechanism of Action The development and enlargement of the prostate gland is dependent on the potent androgen, 5α -dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs. Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ~ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. 12.2 Pharmacodynamics In man, a single 5-mg oral dose of finasteride tablets produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of finasteride 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 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 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