Prescription Drug Information: Dutasteride

DUTASTERIDE- dutasteride capsule, liquid filled
Epic Pharma, LLC

1 INDICATIONS AND USAGE

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, is 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.

2.1 Monotherapy

The recommended dose of dutasteride is 1 capsule (0.5 mg) taken once daily.

2.2 Combination with Alpha-adrenergic Antagonist

The recommended dose of dutasteride 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, opaque, yellow, oblong shape capsules imprinted with “PC23” in red ink.

4 CONTRAINDICATIONS

Dutasteride capsules are contraindicated for use in:

Pregnancy. Dutasteride use is contraindicated in women who are pregnant. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Effects on Prostate-specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride 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 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results.

To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary.

Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy.

5.2 Increased Risk of High-grade Prostate Cancer

In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR®), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.

5.3 Evaluation for Other Urological Diseases

Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.

5.4 Transdermal Exposure of Dutasteride in Pregnant Women—Risk to Male Fetus

Dutasteride capsules should not be handled by women who are pregnant or may be pregnant. Dutasteride can be absorbed through the skin and could result in unintended fetal exposure and potential risk to a male fetus. If a pregnant woman comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)]. Dutasteride can be absorbed through the skin based on animal studies [see Nonclinical Toxicology (13.2)].

5.5 Blood Donation

Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

5.6 Effect on Semen Characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy men throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, compared with placebo, dutasteride treatment resulted in mean reduction in total sperm count, semen volume, and sperm motility; the effects on total sperm count were not reversible after 24 weeks of follow-up. Sperm concentration and sperm morphology were unaffected and mean values for all semen parameters remained within the normal range at all timepoints. The clinical significance of the effect of dutasteride on semen characteristics for an individual patient’s fertility is not known [see Use in Specific Populations (8.3)].

6 ADVERSE REACTIONS

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 Capsules than the Placebo Group (Randomized, Double-blind, Placebo-Controlled Trials Pooled) by Time of Onset

Adverse Reaction

Adverse Reaction Time of Onset

Months 0-6

Months 7-12

Months 13-18

Months 19-24

Dutasteride capsules (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)

Impotencea

Dutasteride capsules

4.7%

1.4%

1.0%

0.8%

Placebo

1.7%

1.5%

0.5%

0.9%

Decreased libidoa

Dutasteride capsules

3.0%

0.7%

0.3%

0.3%

Placebo

1.4%

0.6%

0.2%

0.1%

Ejaculation disordersa

Dutasteride capsules

1.4%

0.5%

0.5%

0.1%

Placebo

0.5%

0.3%

0.1%

0.0%

Breast disordersb

Dutasteride capsules

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.

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