Dutasteride

Warnings and Precautions, Evaluation for Other Urological Diseases ( 5.3 ) 03/2012

1 INDICATIONS AND USAGE Dutasteride capsules is a 5 alpha-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, and • reduce the risk of the need for BPH-related surgery. Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2) Limitations of Use: Dutasteride capsules are not approved for the prevention of prostate cancer. (1.3) 1.1 Monotherapy Dutasteride capsules 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 (AUR), and • reduce the risk of the need for BPH-related surgery. 1.2 Combination With Alpha Adrenergic Antagonist Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.3 Limitations of Use Dutasteride capsules are not approved for the prevention of prostate cancer.

2 DOSAGE AND ADMINISTRATION The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa. Dutasteride capsules may be administered with or without food. Monotherapy: 0.5 mg once daily. (2.1) Combination with tamsulosin: 0.5 mg once daily and tamsulosin 0.4 mg once daily. (2.2) Dosing considerations: Swallow whole. May take with or without food. (2) 2.1 Monotherapy The recommended dose of dutasteride, USP is 1 capsule (0.5 mg) taken once daily. 2.2 Combination With Alpha Adrenergic Antagonist The recommended dose of dutasteride, USP is 1 capsule (0.5 mg) taken once daily and tamsulosin 0.4 mg taken once daily.

3 DOSAGE FORMS AND STRENGTHS 0.5-mg, light brown, oblong, soft gelatin capsule printed with black 'AV5' and containing a clear, slightly yellow to pale amber oily liquid. 0.5-mg soft gelatin capsules ( 3 )

4 CONTRAINDICATIONS Dutasteride, USP is contraindicated for use in: • Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride, USP inhibited development of male fetus external genitalia. Therefore, dutasteride, USP may cause fetal harm when administered to a pregnant woman. If dutasteride, USP is used during pregnancy or if the patient becomes pregnant while taking dutasteride, USP, the patient should be apprised of the potential hazard to the fetus [ see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. • Women of childbearing potential [ see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. • Pediatric patients [ see Use in Specific Populations (8.4) ]. • Patients with previously demonstrated clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride, USP or other 5 alpha-reductase inhibitors [ see Adverse Reactions (6.2) ]. • Pregnancy and women of childbearing potential. (4, 5.4, 8.1 ) • Pediatric patients. (4) • Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride, USP or other 5 alpha-reductase inhibitors. (4)

6 ADVERSE REACTIONS The most common adverse reactions, reported in ≥1% of subjects treated with dutasteride and more commonly than in subjects treated with placebo, are impotence, decreased libido, ejaculation disorders, and breast disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or www.amneal.com 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 with rates in the clinical trial of another drug and may not reflect the rates observed in practice. From clinical trials with dutasteride as monotherapy or in combination with tamsulosin: The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). Monotherapy Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5 mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were white. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo. Table 1. Adverse Reactions Reported in ≥1% of Subjects over a 24-Month Period and More Frequently in the Group Receiving Dutasteride than the Placebo Group (Randomized, Double-blind, Placebo-Controlled Trials Pooled) by Time of Onset Adverse Reaction Dutasteride (n) Adverse Reaction Time of Onset Months 0 to 6 Months 7 to 12 Months 13 to 18 Months 19 to 24 (n = 2,167) (n = 1,901) (n = 1,725) (n = 1,605) Placebo (n) (n = 2,158) (n = 1,922) (n = 1,714) (n = 1,555) Impotence a Dutasteride 4.7% 1.4% 1.0% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a Dutasteride 3.0% 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.1% Ejaculation disorders a Dutasteride 1.4% 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0.0% Breast disorders b Dutasteride 0.5% 0.8% 1.1% 0.6% Placebo 0.2% 0.3% 0.3% 0.1% a These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. b Includes breast tenderness and breast enlargement. Long-term Treatment (Up to 4 Years) High-grad …

7 DRUG INTERACTIONS Use with caution in patients taking potent, chronic cytochrome P450 (CYP)3A4 enzyme inhibitors (e.g., ritonavir). (7) 7.1 Cytochrome P450 3A Inhibitors Dutasteride is extensively metabolized in humans by the cytochrome P450 (CYP)3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology (12.3) ] . 7.2 Alpha-adrenergic Antagonists The administration of dutasteride in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated. 7.3 Calcium Channel Antagonists Co-administration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended [see Clinical Pharmacology (12.3) ] . 7.4 Cholestyramine Administration of a single 5 mg dose of dutasteride followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology (12.3) ] . 7.5 Digoxin Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see Clinical Pharmacology (12.3) ] . 7.6 Warfarin Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Dutasteride is contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4) ] . Dutasteride is not indicated for use in women. Dutasteride is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data) . Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data) . In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats [see Nonclinical Toxicology (13.1) ] . Data Human Data: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. Animal Data: In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day, with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day. In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused sku …

12.1 Mechanism of Action Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

11 DESCRIPTION Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT. Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C 27 H 30 F 6 N 2 O 2 , representing a molecular weight of 528.5 with the following structural formula: Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water. Each dutasteride capsule, administered orally, contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylhydroxytoluene. The inactive excipients are glycerol, gelatin, titanium dioxide, yellow iron oxide, red iron oxide, mono and di-glycerides, butylhydroxytoluene, lecithin, medium chain triglycerides and black ink. The non-volatile ingredients of the black ink are ammonium hydroxide, black iron oxide, propylene glycol and shellac. Chemical Structure

10 OVERDOSAGE In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.

16 HOW SUPPLIED/STORAGE AND HANDLING Dutasteride Capsules 0.5 mg are supplied as opaque, yellow, oblong soft gelatin capsules imprinted with “A 75”. They are available as follows: Bottles of 30: NDC 71205-039-30 Bottles of 60: NDC 71205-039-60 Bottles of 90: NDC 71205-039-90 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Dutasteride, USP is absorbed through the skin. Dutasteride capsules should not be handled by women who are pregnant or who could become pregnant because of the potential for absorption of dutasteride, USP and the subsequent potential risk to a developing male fetus [ see Warnings and Precautions (5.4) ]. Distributed by: Amneal Pharmaceuticals Bridgewater, NJ 08807 Rev. 10-2015-01 Relabeled By; Proficient Rx LP Thousand Oaks CA 91320