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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 AVODART as monotherapy or in combination with tamsulosin:
- The most common adverse reactions reported in subjects receiving AVODART 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 (AVODART 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 AVODART (2%) or tamsulosin (4%) as monotherapy.
- Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving AVODART and 3% of subjects receiving placebo in placebo-controlled trials with AVODART. 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 (AVODART plus tamsulosin) and 4% of subjects receiving AVODART or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).
Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of AVODART 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 AVODART, 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 AVODART 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 AVODART 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
AVODART Than the Placebo Group (Randomized, Double-Blind, Placebo-Controlled
Trials Pooled) by Time of Onset
|Adverse Reaction Time of Onset|
(n = 2,167)
(n = 2,158)
(n = 1,901)
(n = 1,922)
(n = 1,725)
(n = 1,714)
(n = 1,605)
(n = 1,555)
|aThese 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.
bIncludes 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 AVODART (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 AVODART (1.0%) compared with men on placebo (0.5%) [seeINDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS]. 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 AVODART.
Reproductive and Breast Disorders
In the 3 pivotal placebo-controlled BPH trials with AVODART, 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 AVODART, 0.4-mg tamsulosin, or combination therapy (0.5-mg AVODART plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with AVODART; 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 AVODART 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
AVODART or Tamsulosin (CombAT) by Time of Onset
|Adverse Reaction||Adverse Reaction Time of Onset|
|Combinationa AVODART Tamsulosin||Year 1||Year 2
(n = 1,428)
(n = 1,464)
(n = 1,468)
(n = 1,283)
(n = 1,325)
(n = 1,281)
(n = 1,200)
(n = 1,200)
(n = 1,112)
(n = 1,610)
(n = 1,623)
(n = 1,611)
(n = 1,527)
(n = 1,548)
(n = 1,545)
|AVODART||0.50%||0.30%||0.10%||< 0.1%||< 0.1%|
|aCombination = AVODART 0.5 mg once daily plus tamsulosin 0.4
mg once daily.
bIncludes 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.
dIncludes erectile dysfunction and disturbance in sexual arousal.
eIncludes 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: AVODART, 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 AVODART in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking AVODART 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 AVODART 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.
The following adverse reactions have been identified during post-approval use of AVODART. 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 AVODART.
Neoplasms: Male breast cancer.
Psychiatric Disorders: Depressed mood.
Reproductive System and Breast Disorders: Testicular pain and testicular swelling.
Read the Avodart (dutasteride) Side Effects Center for a complete guide to possible side effects
Cytochrome P450 3A Inhibitors
Dutasteride is extensively metabolized in humans by the CYP3A4 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 AVODART to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see CLINICAL PHARMACOLOGY].
Alpha Adrenergic Antagonists
The administration of AVODART 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.
Calcium Channel Antagonists
Coadministration 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].
Administration of a single 5-mg dose of AVODART followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride [see CLINICAL PHARMACOLOGY].
AVODART 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].
Concomitant administration of AVODART 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].
Read the Avodart Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/16/2013
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