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 to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Monotherapy

• The most common adverse reactions reported in subjects receiving AVODART were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders.
• Study withdrawal due to adverse reactions occurred in 4% of subjects receiving AVODART and 3% of subjects receiving placebo. The most common adverse reaction leading to study withdrawal was impotence (1%).

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 studies, each with 2-year open-label extensions. 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% 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 Studies Pooled) by Time of Onset

Long-Term Treatment (Up to 4 Years): There is no evidence of increased drug-related sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. The relationship between long-term use of AVODART and male breast neoplasia is currently unknown.

Combination with Alpha-Blocker Therapy (CombAT)

• 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. Over 2 years of treatment, drug-related ejaculation disorders occurred more frequently in subjects receiving combination therapy (9%) compared to AVODART (2%) or tamsulosin (3%) as monotherapy.
• Study withdrawal due to adverse reactions occurred in 5% of subjects receiving combination therapy (AVODART plus tamsulosin) and 3% of subjects receiving AVODART or tamsulosin as monotherapy. The most common adverse reaction leading to study withdrawal in subjects receiving combination therapy was impotence (1%).

Over 4,800 male subjects with BPH were randomly assigned to receive either 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 study. Adverse reaction information over the first 2 years of treatment is presented below; information for years 2 to 4 is not yet available as the study is ongoing. During the first 2 years, 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% Caucasian. Table 2 summarizes adverse reactions reported in at least 1% of subjects in any treatment group.

Table 2. Adverse Reactions Reported Over a 24-Month Period in ≥ 1% of Subjects in Any Treatment Group (CombAT) by Time of Onset

Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

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

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 Blocking Agents

The administration of AVODART in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha-adrenergic blocker. 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].

Cholestyramine

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].

Digoxin

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].

Warfarin

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].

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