Finasteride

1 INDICATIONS & USAGE Finasteride tablets USP are indicated for the treatment of male pattern hair loss (androgenetic alopecia) in MEN ONLY. Efficacy in bitemporal recession has not been established. Finasteride tablets USP are not indicated for use in women. • Finasteride tablets USP are 5α-reductase inhibitors indicated for the treatment of male pattern hair loss (androgenetic alopecia) in MEN ONLY ( 1 ). • Finasteride tablets USP are not indicated for use in women ( 1 , 4 , 5.1 ).

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 distinct isozymes are found in mice, rats, monkeys, and humans: Type I and II. Each of these isozymes is differentially expressed in tissues and developmental stages. In humans, Type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5α-reductase is responsible for approximately one-third of circulating DHT. The Type II 5α-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 5α-reductase over Type I isozyme (IC 50 =500 and 4.2 nM for Type I and II, respectively). For both isozymes, the inhibition by finasteride is accompanied by reduction of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t 1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex). Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting 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.

2 DOSAGE & ADMINISTRATION Finasteride tablets USP may be administered with or without meals. The recommended dose of finasteride tablets USP is one tablet (1 mg) taken once daily. In general, daily use for three months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit, which should be re-evaluated periodically. Withdrawal of treatment leads to reversal of effect within 12 months. • Finasteride tablets USP may be administered with or without meals ( 2 ). • One tablet (1 mg) taken once daily ( 2 ). • In general, daily use for three months or more is necessary before benefit is observed ( 2 ).

6 ADVERSE REACTIONS The most common adverse reactions, reported in ≥1% of patients treated with finasteride tablets USP and greater than in patients treated with placebo are: decreased libido, erectile dysfunction and ejaculation disorder ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 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 Tablets USP 1 mg in the Treatment of Male Pattern Hair Loss In three controlled clinical trials for finasteride tablets USP of 12-month duration, 1.4% of patients taking finasteride tablets USP (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 USP or placebo are presented in Table 1. TABLE 1 Drug-Related Adverse Experiences for Finasteride Tablets USP, 1 mg in Year 1 (%) MALE PATTERN HAIR LOSS Finasteride tablets USP 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 tablets USP 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 USP 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 USP. 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 USP (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 USP, 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 tablets USP, 5 mg and AVODART (dutasteride) in the Treatment of Benign Prostatic Hyperplasia In the finasteride tablets USP, 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 USP, 5 mg/day and 1516 on placebo). 3.7% (57 patients) treated with finasteride tablets USP, 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 tablets USP, 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

5 WARNINGS AND PRECAUTIONS Finasteride tablets USP are not indicated for use in women or pediatric patients ( 5.1 , 5.4 ). • Women should not handle crushed or broken finasteride tablets USP when they are pregnant or may potentially be pregnant due to potential risk to a male fetus ( 5.1 , 8.1 , 16 ). • Finasteride tablets USP causes a decrease in serum PSA levels. Any confirmed increase in PSA while on finasteride tablets USP 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 ( 5.2 ). • 5α-reductase inhibitors may increase the risk of high-grade prostate cancer ( 5.3 , 6.1 ). 5.1 Exposure of Women - Risk to Male Fetus Finasteride tablets USP are not indicated for use in women. Women should not handle crushed or broken finasteride tablets USP, 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 USP are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. [S ee Indications and Usage (1) , Contraindications (4) , Use in Specific Populations (8.1) , How Supplied/Storage and Handling (16) and Patient Counseling Information (17.1) . ] 5.2 Effects on Prostate Specific Antigen (PSA) In clinical studies with finasteride tablets USP in men 18 to 41 years of age, the mean value of serum prostate specific antigen (PSA) decreased from 0.7 ng/mL at baseline to 0.5 ng/mL at Month 12. Further, in clinical studies with finasteride tablets USP 5 mg when used in older men who have benign prostatic hyperplasia (BPH), PSA levels are decreased by approximately 50%. Other studies with finasteride tablets USP 5 mg showed it may also cause decreases in serum PSA in the presence of prostate cancer. These findings should be taken into account for proper interpretation of serum PSA when evaluating men treated with finasteride. Any confirmed increase from the lowest PSA value while on finasteride tablets USP 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 to therapy with finasteride tablets USP may also affect PSA test results. 5.3 Increased Risk of High-Grade Prostate Cancer with 5-Reductase Inhibitors Men aged 55 and over with a normal digital rectal examination and PSA ≤3 ng/mL at baseline taking finasteride 5 mg/day (5 times the dose of finasteride tablets USP 1 mg) 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 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 USP are not indicated for use in pediatric patients [ see Use in Specific Populations (8.4) ].

4 CONTRAINDICATIONS Finasteride tablets USP are contraindicated in the following: • Pregnancy. Finasteride use is contraindicated in women 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 woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. [ See Warnings and Precautions (5.1) , Use in Specific Populations (8.1) , How Supplied/Storage and Handling (16) and Patient Counseling Information (17.1) .] In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring. • Hypersensitivity to any component of this medication. • Pregnancy ( 4 , 5.1 , 8.1 , 16 ). • Hypersensitivity to any components of this product ( 4 ).

10 OVERDOSAGE In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions. Until further experience is obtained, no specific treatment for an overdose with finasteride can be recommended. Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m 2 (500 mg/kg)and in female and male rats at single oral doses of 2360 mg/m 2 (400 mg/kg)and 5900 mg/m 2 (1000 mg/kg), respectively.