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AVODART®
(dutasteride)
Soft Gelatin Capsules
DESCRIPTION
AVODART (dutasteride) is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT).
Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula:
Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.
AVODART Soft Gelatin Capsules for oral administration contain 0.5 mg of the active ingredient dutasteride in yellow capsules with red print. Each capsule contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are gelatin (from certified BSE-free bovine sources), glycerin, and ferric oxide (yellow). The soft gelatin capsules are printed with edible red ink.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Pharmacokinetics
Special Populations
Drug Interactions
In vitro drug metabolism studies reveal that dutasteride is metabolized by the human cytochrome P450 isoenzymes CYP3A4 and CYP3A5. In a human mass balance analysis (n = 8), dutasteride was extensively metabolized. Less than 20% of the dose was excreted unchanged in the feces. No clinical drug interaction studies have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on the in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin, terazosin, warfarin, digoxin, and cholestyramine (see PRECAUTIONS: Drug Interactions).
Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.
CLINICAL STUDIES
Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind studies, each with 2-year open-label extensions (n = 2,340). More than 90% of the study population was Caucasian. Subjects were at least 50 years of age with a serum prostate-specific antigen (PSA) ≥1.5 ng/mL and <10 ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4,325 subjects randomly assigned to receive either dutasteride or placebo completed 2 years of double-blind treatment (70% and 67%, respectively). Most of the 2,340 subjects in the study extensions completed 2 additional years of open-label treatment (71%).
Effect on Symptom Scores
Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35. The baseline AUA-SI score across the 3 studies was approximately 17 units in both treatment groups.
Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in one study and by Month 12 in the other 2 pivotal studies. At Month 12, the mean decrease from baseline in AUA-SI symptom scores across the 3 studies pooled was -3.3 units for dutasteride and -2.0 units for placebo with a mean difference between the 2 treatment groups of -1.3 (range, -1.1 to -1.5 units in each of the 3 studies, p<0.001) and was consistent across the 3 studies. At Month 24, the mean decrease from baseline was -3.8 units for dutasteride and -1.7 units for placebo with a mean difference of -2.1 (range, -1.9 to -2.2 units in each of the 3 studies, p<0.001). See Figure 1. The improvement in BPH symptoms seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension studies.
These studies were prospectively designed to evaluate effects on symptoms based on prostate size at baseline. In men with prostate volumes ≥40 cc, the mean decrease was -3.8 units for dutasteride and -1.6 units for placebo, with a mean difference between the 2 treatment groups of -2.2 at Month 24. In men with prostate volumes <40 cc, the mean decrease was -3.7 units for dutasteride and -2.2 units for placebo, with a mean difference between the 2 treatment groups of -1.5 at Month 24.
*AUA-SI score ranges from 0 to 35.
Effect on Acute Urinary Retention and the Need for Surgery
Efficacy was also assessed after 2 years of treatment by the incidence of acute urinary retention (AUR) requiring catheterization and BPH-related urological surgical intervention. Compared with placebo, AVODART was associated with a statistically significantly lower incidence of AUR (1.8% for AVODART vs. 4.2% for placebo, p<0.001; 57% reduction in risk, 95% CI: [38-71%]) and with a statistically significantly lower incidence of surgery (2.2% for AVODART vs. 4.1% for placebo, p<0.001; 48% reduction in risk, 95% CI: [26-63%]). See Figures 2 and 3.
Effect on Prostate Volume
A prostate volume of at least 30 cc measured by transrectal ultrasound was required for study entry. The mean prostate volume at study entry was approximately 54 cc.
Statistically significant differences (dutasteride vs. placebo) were noted at the earliest post-treatment prostate volume measurement in each study (Month 1, Month 3, or Month 6) and continued through Month 24. At Month 12, the mean percent change in prostate volume across the 3 studies pooled was -24.7% for dutasteride and -3.4% for placebo; the mean difference (dutasteride minus placebo) was -21.3% (range, -21.0% to -21.6% in each of the 3 studies, p<0.001). At Month 24, the mean percent change in prostate volume across the 3 studies pooled was -26.7% for dutasteride and -2.2% for placebo with a mean difference of -24.5% (range, -24.0% to -25.1% in each of the 3 studies, p<0.001). See Figure 4. The reduction in prostate volume seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension studies.
Effect on Maximum Urine Flow Rate
A mean peak urine flow rate (Qmax) of≤15 mL/sec was required for study entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal studies.
Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 studies and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 studies pooled was 1.6 mL/sec for dutasteride and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range, 0.7 to 1.0 mL/sec in each of the 3 studies, p<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range, 1.0 to 1.2 mL/sec in each of the 3 studies, p<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension studies.
Summary of Clinical Studies
Data from 3 large, well-controlled efficacy studies demonstrate that treatment with AVODART (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume, and increases maximum urinary flow rates. These data suggest that AVODART arrests the disease process of BPH in men with an enlarged prostate.
INDICATIONS AND USAGE
AVODART is 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
- Reduce the risk of the need for BPH-related surgery
CONTRAINDICATIONS
AVODART is contraindicated for use in women and children.
AVODART is contraindicated for patients with known hypersensitivity (e.g., angioedema) to dutasteride, other 5α-reductase inhibitors, or any component of the preparation.
WARNINGS
Exposure of Women—Risk to Male Fetus
Dutasteride is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle AVODART Soft Gelatin Capsules because of the possibility of absorption of dutasteride and the potential risk of a fetal anomaly to a male fetus (see CONTRAINDICATIONS). In addition, women should use caution whenever handling AVODART Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.
PRECAUTIONS
General
Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with AVODART. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5α-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy.
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.
Use in Hepatic Impairment
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized and has a half-life of approximately 5 weeks at steady state, caution should be used in the administration of dutasteride to patients with liver disease.
Use with Potent CYP3A4 Inhibitors
Although dutasteride is extensively metabolized, no metabolically based drug interaction studies have been conducted. The effect of potent CYP3A4 inhibitors has not been studied. Because of the potential for drug-drug interactions, care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir).
Effects on Prostate-Specific Antigen and Prostate Cancer Detection
Digital rectal examinations, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with AVODART and periodically thereafter.
Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and approximately 50% following 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Therefore, for interpretation of serial PSAs in a man taking AVODART, a new baseline PSA concentration should be established after 3 to 6 months of treatment, and this new value should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with AVODART for 6 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 at Month 12, even under the influence of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary.
Information for Patients
Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with AVODART and to reread it upon prescription renewal for new information regarding the use of AVODART.
AVODART Soft Gelatin Capsules should not be handled by a woman who is pregnant or who may become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus (see CONTRAINDICATIONS and WARNINGS: Exposure of Women—Risk to Male Fetus).
Physicians should inform patients that ejaculate volume might be decreased in some patients during treatment with AVODART. This decrease does not appear to interfere with normal sexual function. In clinical trials, impotence and decreased libido, considered by the investigator to be drug-related, occurred in a small number of patients treated with AVODART or placebo (see ADVERSE REACTIONS: Table 1).
Men treated with dutasteride should not donate blood until at least 6 months have passed following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion (see PRECAUTIONS: Blood Donation).
Drug Interactions
Care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors (see PRECAUTIONS: Use with Potent CYP3A4 Inhibitors).
Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans. In vitro studies demonstrate that dutasteride does not displace warfarin, diazepam, or phenytoin from plasma protein binding sites, nor do these model compounds displace dutasteride.
Drug/Laboratory Test Interactions
Central Nervous System Toxicity
In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposure 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Pregnancy Category X (see CONTRAINDICATIONS). AVODART is contraindicated for use in women. AVODART has not been studied in women because preclinical data suggest that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs in a male fetus carried by a woman exposed to dutasteride.
In an intravenous embryo-fetal development study in the rhesus monkey (12/group), administration of dutasteride at 400, 780, 1,325, or 2,010 ng/day on gestation days 20 to 100 did not adversely affect development of male external genitalia. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed in monkeys treated with the highest dose. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times based on blood levels of parent drug (32 to 186 times based on a ng/kg daily dose) the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. Dutasteride is highly bound to proteins in human semen (>96%), potentially reducing the amount of dutasteride available for vaginal absorption.
In an embryo-fetal development study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in feminization of male fetuses (decreased anogenital distance) and male offspring (nipple development, hypospadias, and distended preputial glands) at all doses (0.07- to 111-fold the expected male clinical exposure). An increase in stillborn pups was observed at 30 mg/kg/day, and reduced fetal body weight was observed at doses≥2.5 mg/kg/day (15- to 111-fold the expected clinical exposure). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses of 12.5 and 30 mg/kg/day (56- to 111-fold the expected clinical exposure).
In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of F1 generation male offspring occurred at doses ≥2.5 mg/kg/day (14- to 90-fold the expected clinical exposure in men). At a daily dose of 0.05 mg/kg/day (0.05-fold the expected clinical exposure), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and decrease prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day.
Feminization of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5α-reductase inhibitors. These results are similar to observations in male infants with genetic 5α-reductase deficiency.
In the rabbit, embryo-fetal study doses of 30, 100, and 200 mg/kg (28- to 93-fold the expected clinical exposurein men) were administered orally on days 7 to 29 of pregnancy to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at doses of 0.05, 0.4, 3.0, and 30 mg/kg/day (0.3- to 53-fold the expected clinical exposure) also produced evidence of feminization of the genitalia in male fetuses at all doses. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.
Nursing Mothers
AVODART is not indicated for use in women. It is not known whether dutasteride is excreted in human breast milk.
Pediatric Use
AVODART is not indicated for use in the pediatric population. Safety and effectiveness in the pediatric population have not been established.
Geriatric Use
Of 2,167 male subjects treated with AVODART in 3 clinical studies, 60% were 65 and over and 15% were 75 and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
ADVERSE REACTIONS
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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Most adverse reactions were mild or moderate and generally resolved while on treatment in both the AVODART and placebo groups. The most common adverse events leading to withdrawal in both treatment groups were associated with the reproductive system.
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. Over the 2-year double-blind treatment period, 376 subjects (9% of each treatment group) were withdrawn from the studies due to adverse experiences, most commonly associated with the reproductive system, with similar findings during the 2-year open-label extensions. Withdrawals due to adverse events considered by the investigator to have a reasonable possibility of being caused by the study medication occurred in 4% of the subjects receiving AVODART and in 3% of the subjects receiving placebo. Table 1 summarizes clinical adverse reactions that were reported by the investigator as drug-related in at least 1% of subjects receiving AVODART and at a higher incidence than subjects receiving placebo.
Adverse Events Dutasteride (n) Placebo (n) | Adverse Event Onset | |||
Month 0-6 (n = 2,167) (n = 2,158) | Month 7-12 (n = 1,901) (n = 1,922) | Month 13-18 (n = 1,725) (n = 1,714) | Month 19-24 (n = 1,605) (n = 1,555) | |
Impotence Dutasteride Placebo | 4.7% 1.7% | 1.4% 1.5% | 1.0% 0.5% | 0.8% 0.9% |
Decreased libido Dutasteride Placebo | 3.0% 1.4% | 0.7% 0.6% | 0.3% 0.2% | 0.3% 0.1% |
Ejaculation disorder Dutasteride Placebo | 1.4% 0.5% | 0.5% 0.3% | 0.5% 0.1% | 0.1% 0.0% |
Gynecomastia† Dutasteride Placebo | 0.5% 0.2% | 0.8% 0.3% | 1.1% 0.3% | 0.6% 0.1% |
*A drug-related adverse event is one considered by the investigator to have a reasonable possibility of being caused by the study medication. In assessing causality, investigators were asked to select from 1 of 2 options: reasonably related to study medication or unrelated to study medication.
†Includes breast tenderness and breast enlargement.
Long-Term Treatment (Up to 4 Years)
There is no evidence of increased drug-related sexual adverse events (impotence, decreased libido and ejaculation disorder) or gynecomastia with increased duration of treatment. The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.
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 possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) potential causal connection to AVODART.
- allergic reactions, including rash, pruritus, urticaria, localized edema, angioedema.
OVERDOSAGE
In volunteer studies, 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 study, 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.
DOSAGE AND ADMINISTRATION
The recommended dose of AVODART is 1 capsule (0.5 mg) taken orally once a day. The capsules should be swallowed whole and not chewed or opened, as contact with the capsule spans may result in irritation of the oropharyngeal mucosa. AVODART may be administered with or without food.
No dosage adjustment is necessary for subjects with renal impairment or for the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Geriatric and Renal Impairment). Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made (see PRECAUTIONS: General).
HOW SUPPLIED
AVODART Soft Gelatin Capsules 0.5 mg are oblong, opaque, dull yellow, gelatin capsules imprinted with “GX CE2” in red ink on one side packaged in bottles of 30 (NDC 0173-0712-15) and 90 (NDC 0173-0712-04) with child-resistant closures.
Storage and Handling
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Dutasteride is absorbed through the skin. AVODART Soft Gelatin capsules should not be handled by women who are pregnant or who may become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus (see CLINICAL PHARMACOLOGY: Pharmacokinetics, WARNINGS: Exposure of Women—Risk to Male Fetus, and PRECAUTIONS: Information for Patients and Pregnancy).
Manufactured by Catalent Pharma Solutions
Beinheim, France for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2007, GlaxoSmithKline. All rights reserved.
October 2007 AVT:1PI