Finasteride

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

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 ).

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 between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder. TABLE 2 Drug-Related Adverse Experiences for finasteride tablets USP, 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 tablets USP, 5 mg and PLESS were similar. There is no evidence of increased sexual adverse experiences with increased duration of treatment with finasteride tablets USP, 5 mg. New reports of drug-related sexual adverse experiences decreased with duration of ther

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 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.