DUTASTERIDE

DUTASTERIDE- dutasteride capsule, liquid filled
Rising Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Monotherapy

DUTASTERIDE (dutasteride) soft gelatin 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 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 is 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 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, dull yellow, gelatin capsules imprinted with “D05” in black ink on one side.

4 CONTRAINDICATIONS

DUTASTERIDE is contraindicated for use in:

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 Exposure of Women—Risk to Male Fetus

DUTASTERIDE Capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant 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) ].

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 normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.

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 than the Placebo Group (Randomized, Double-blind, Placebo-controlled Trials Pooled) by Time of Onset
*
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.
Includes breast tenderness and breast enlargement.
Adverse Reaction Time of Onset
Adverse Reaction Months 0-6 Months 7-12 Months 13-18 Months 19-24
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 *
DUTASTERIDE 4.7% 1.4% 1.0% 0.8%
Placebo 1.7% 1.5% 0.5% 0.9%
Decreased libido *
DUTASTERIDE 3.0% 0.7% 0.3% 0.3%
Placebo 1.4% 0.6% 0.2% 0.1%
Ejaculation disorders *
DUTASTERIDE 1.4% 0.5% 0.5% 0.1%
Placebo 0.5% 0.3% 0.1% 0.0%
Breast disorders
DUTASTERIDE 0.5% 0.8% 1.1% 0.6%
Placebo 0.2% 0.3% 0.3% 0.1%

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 white. 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 (1.0%) 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), 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 white. 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 Coadministration Therapy Group than the Groups Receiving Monotherapy with DUTASTERIDE or Tamsulosin (CombAT) by Time of Onset
*
Combination = DUTASTERIDE 0.5 mg once daily plus tamsulosin 0.4 mg once daily.
Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation.
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.
§
Includes erectile dysfunction and disturbance in sexual arousal.
Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction.
#
Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling.
Adverse Reaction Time of Onset
Year 1
Adverse Reaction Months 0-6 Months 7-12 Year 2 Year 3 Year 4
Combination * (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 ,
Combination 7.8% 1.6% 1.0% 0.5% <0.1%
DUTASTERIDE 1.0% 0.5% 0.5% 0.2% 0.3%
Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3%
Impotence , §
Combination 5.4% 1.1% 1.8% 0.9% 0.4%
DUTASTERIDE 4.0% 1.1% 1.6% 0.6% 0.3%
Tamsulosin 2.6% 0.8% 1.0% 0.6% 1.1%
Decreased libido ,
Combination 4.5% 0.9% 0.8% 0.2% 0.0%
DUTASTERIDE 3.1% 0.7% 1.0% 0.2% 0.0%
Tamsulosin 2.0% 0.6% 0.7% 0.2% <0.1%
Breast disorders #
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% 0.0%
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% 0.0%

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.

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