Avodart Drug Information

• 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. AVODART may be administered with or without food.
• Monotherapy: 0.5 mg once daily. ( 2.1 )
• Combination with tamsulosin: 0.5 mg once daily and tamsulosin 0.4 mg once daily. ( 2.2 )
• Dosing considerations: Swallow whole. May take with or without food. ( 2 ) 2.1 Monotherapy The recommended dose of AVODART is 1 capsule (0.5 mg) taken once daily. 2.2 Combination with Alpha-adrenergic Antagonist The recommended dose of AVODART is 1 capsule (0.5 mg) taken once daily and tamsulosin 0.4 mg taken once daily.

• The most common adverse reactions, reported in ≥1% of subjects treated with AVODART 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 Waylis Therapeutics LLC at 888-514-4727 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 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%). Monotherapy 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 white. 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 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. Adverse Reaction Adverse Reaction Time of Onset Months 0 ‑ 6 Months 7 ‑ 12 Months 13 ‑ 18 Months 19 ‑ 24 AVODART (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 AVODART 4.7% 1.4% 1.0% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a AVODART 3.0% 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.1% Ejaculation disorders a AVODART 1.4% 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0.0% Breast disorders b AVODART 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 AVODART (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 AVODART (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 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 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 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 a Combination = AVODART 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. Adverse Reaction Adverse Reaction Time of Onset Year 1 Months 0 ‑ 6 Months 7 ‑ 12 Year 2 Year 3 Year 4 Combination a (n = 1,610) (n = 1,527) (n = 1,428) (n = 1,283) (n = 1,200) AVODART (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% 0.5% <0.1% AVODART 1.0% 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% AVODART 4.0% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1.0% 0.6% 1.1% Decreased libido c,e Combination 4.5% 0.9% 0.8% 0.2% 0.0% AVODART 3.1% 0.7% 1.0% 0.2% 0.0% 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% AVODART 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% AVODART 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: 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. 6.2 Postmarketing Experience 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. 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.

Cytochrome P450 3A Inhibitors Dutasteride is extensively metabolized in humans by the

cytochrome P450 (CYP)3A4 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) .

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 .

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 .

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 .

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 .

Pregnancy Risk Summary AVODART is contraindicated for use in pregnancy because it may cause harm to the male fetus . AVODART is not indicated for use in women. AVODART is a 5 alpha‑reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion.

These results are similar to observations in male infants with genetic 5 alpha‑reductase deficiency. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity.

At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data). Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats . Data Human Data: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of a 50‑kg woman to 5 mL of semen and 100% absorption, the woman’s expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies.

Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. Animal Data: In an embryo‑fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day, with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day.

In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development ) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity. In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner.

Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50‑kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption.

The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. In an oral pre- and post-natal development study in rats, feminization of the male genitalia was observed.

Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with a lack of a no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with a no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, a decrease in time to vaginal patency for female offspring, and a decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity ).

Pediatric Use AVODART is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.

• is 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, AVODART 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 AVODART or other 5 alpha-reductase inhibitors [see Adverse Reactions ( 6.2 )] .
• Pregnancy. Dutasteride use is contraindicated in women who are pregnant. ( 4 , 5.4 , 8.1 )
• Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to AVODART or other 5 alpha-reductase inhibitors.( 4 )

In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride.

Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.