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.

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 three 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 Caucasian.

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 Reactions Adverse Reaction Time of Onset Months 0 to 6 Months 7 to 12 Months 13 to 18 Months 19 to 24 Dutasteride (n) (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% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a Dutasteride 3% 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% 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-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months.

Subjects were randomized to receive placebo (N = 4,126) or 0.5 mg daily doses of dutasteride (N = 4,105) for up to 4 years.

The mean age was 63 years and 91% were Caucasian.

Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated.

There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride (1%) compared with men on placebo (0.5%) [ see Indications and Usage (1.3) , Warnings and Precautions (5.2) ].

In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR 1 ), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride.

Reproductive and Breast Disorders: In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido and ejaculation disorder) or breast disorders with increased duration of treatment.

Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group.

No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.

The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.

Combination With Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin, or combination therapy (0.5 mg dutasteride plus 0.4 mg tamsulosin) administered once daily in a 4-year double-blind trial.

Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy.

The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian.

Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride or tamsulosin.

Table 2.

Adverse Reactions Reported Over a 48-Month Period in ≥1% of Subjects and More Frequently in the Co-administration Therapy Group Than the Groups Receiving Monotherapy With Dutasteride or Tamsulosin (CombAT) by Time of Onset Adverse Reaction Adverse Reaction Time of Onset Year 1 Year 2 Year 3 Year 4 Months 0 to 6 Months 7 to 12 Combination a (n = 1,610) (n = 1,527) (n = 1,428) (n = 1,283) (n = 1,200) Dutasteride (n = 1,623) (n = 1,548) (n = 1,464) (n = 1,325) (n = 1,200) Tamsulosin (n = 1,611) (n = 1,545) (n = 1,468) (n = 1,281) (n = 1,112) Ejaculation disorders b,c Combination 7.8% 1.6% 1% 0.5% <0.1% Dutasteride 1% 0.5% 0.5% 0.2% 0.3% Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3% Impotence c,d Combination 5.4% 1.1% 1.8% 0.9% 0.4% Dutasteride 4% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1% 0.6% 1.1% Decreased libido c,e Combination 4.5% 0.9% 0.8% 0.2% 0% Dutasteride 3.1% 0.7% 1.0% 0.2% 0% Tamsulosin 2.0% 0.6% 0.7% 0.2% <0.1% Breast disorders f Combination 1.1% 1.1% 0.8% 0.9% 0.6% Dutasteride 0.9% 0.9% 1.2% 0.5% 0.7% Tamsulosin 0.4% 0.4% 0.4% 0.2% 0% Dizziness Combination 1.1% 0.4% 0.1% <0.1% 0.2% Dutasteride 0.5% 0.3% 0.1% <0.1% <0.1% Tamsulosin 0.9% 0.5% 0.4% <0.1% 0% a Combination = Dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure and premature ejaculation.

c 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.

d Includes erectile dysfunction and disturbance in sexual arousal.

e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction.

f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain and nipple swelling.

Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%).

Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer.

The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo.

A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure.

Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown.

No causal relationship between dutasteride alone or in combination with tamsulosin and cardiac failure has been established.

No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dutasteride.

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.

These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to dutasteride.

Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions and angioedema.

Neoplasms: Male breast cancer.

Psychiatric Disorders: Depressed mood.

Reproductive System and Breast Disorders: Testicular pain and testicular swelling.