SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 13 STORAGE AND STABILITY 15 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 16

PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 17 DETAILED PHARMACOLOGY 30 TOXICOLOGY 31 REFERENCES 35

PART III: CONSUMER INFORMATION. 37

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

AVODART(tm) (dutasteride) soft gelatin capsules are contraindicated for use in women and children (see WARNINGS AND PRECAUTIONS, Exposure of Women-Risk to Male Fetus). AVODART(tm) is contraindicated in patients with known hypersensitivity to dutasteride, other 5 alpha-reductase inhibitors, or any component of the preparation.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions AVODARTTM is for use for men only.

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(tm) soft gelatin capsules.

Prior to treatment with AVODART(tm), patients should be assessed thoroughly to rule out other urological diseases including prostate cancer. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be proper candidates for 5 alpha-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy. No study has been conducted to determine if AVODART(tm) can be used for the control of BPH in asymptomatic patients. The long-term (> 4 years) beneficial and adverse effects of AVODART(tm) have not been established.

Hormone Levels

In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline- adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (3.37 nmol/L, p < 0.003) and thyroid-stimulating hormone (TSH) at 52 weeks (0.4 mcIU/mL, p < 0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for TSH at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and TSH had returned to baseline in the group of subjects with available data at the visit. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range. In patients with BPH treated with dutasteride in a large Phase III trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.

Men 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.

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized and has a half-life of 3 to 5 weeks, caution should be used in the administration of dutasteride to patients with liver disease.

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 reduction 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%), two 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.

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(tm) Soft Gelatin Capsules because of the possibility of absorption of dutasteride and the potential risk of a fetal anomaly to a male fetus. Pre-clinical data suggests that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs in a male foetus carried by a woman exposed to dutasteride (see TOXICOLOGY). In addition, women should use caution whenever handling AVODART(tm) Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water. It is not known whether dutasteride is excreted in human milk.

Nursing Women:

Pediatrics

: BPH is not a disease of childhood. AVODART(tm) is not indicated for use in children. Safety and effectiveness in children have not been established. Dutasteride is absorbed through the skin and therefore contact with leaking capsules must be avoided. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Geriatrics

: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5 mg dose of dutasteride. In this single dose study, dutasteride half life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal studies, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Effects on Prostate Specific Antigen (PSA) and Prostate Cancer Detection

Digital rectal examination, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with AVODART(tm) (dutasteride) soft gelatin capsules and periodically thereafter.

Serum prostate-specific antigen (PSA) concentration is an important component of the screening process to detect prostate cancer. Generally, a total serum PSA concentration greater than 4 ng/mL (Hybritech) requires further evaluation and consideration of prostate biopsy. Physicians should be aware that a baseline PSA less than 4 ng/mL in patients taking AVODART(tm) does not exclude a diagnosis of prostate cancer. Dutasteride causes a decrease in serum PSA levels by approximately 50%, after 6 months, in patients with BPH, even in the presence of prostate cancer. Although there may be individual variation, the reduction in PSA by approximately 50% is predictable as it was observed over the entire range of baseline PSA values (1.5 to 10 ng/mL). Therefore, to interpret an isolated PSA value in a man treated with AVODART(tm) for six months or more, PSA values should be doubled (e.g. : Multiplied by a factor of 2) for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer. Any sustained increases in PSA levels while on AVODART(tm) should be carefully evaluated to rule out prostate cancer. Total serum PSA levels return to baseline within 6 months of discontinuing treatment with AVODART(tm). The ratio of free to total PSA remains constant even under the influence of AVODART(tm). If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing AVODART(tm) therapy, no adjustment to its value appears necessary. Co-administration of tamsulosin with dutasteride resulted in similar changes to total PSA as dutasteride monotherapy after 2 years.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Most adverse reactions were mild or moderate and generally resolved while on treatment in both the AVODART(tm) and placebo groups. The most common adverse events leading to withdrawal in both treatment groups were associated with the reproductive system.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Dutasteride Monotherapy

Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5 mg daily doses of AVODART(tm) 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(tm), 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(tm) 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(tm) 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(tm) and at a higher incidence than subjects receiving placebo.

Table 1 Drug-Related Adverse Events * Reported in >= 1% Subjects Over a 48- Month Period and More Frequently in the Dutasteride Group Than the Placebo Group (Pivotal Studies Pooled)

	Adverse Event Onset
	Double-Blind				Open-Label * *
Adverse Events	Month 0-6	Month 7-12	Month 13-18	Month 19-24	Month 25-36	Month 39-48
Dutasteride (n)	(n = 2167)	(n = 1901)	(n = 1725)	(n = 1605)	(n = 1188)	(n = 1041)
Placebo (n)	(n = 2158)	(n = 1922)	(n = 1714)	(n = 1555)	(n = 1152)	(n = 968)
Impotence	4.7%	1.4%	1.0%	0.8%	1.4%	0.4%
Dutasteride	4.7%	1.4%	1.0%	0.8%	1.4%	0.4%
Placebo	1.7%	1.5%	0.5%	0.9%	2.8%	0.4%
Decreased libido	3.0%	0.7%	0.3%	0.3%	0.4%	0.1%
Dutasteride	3.0%	0.7%	0.3%	0.3%	0.4%	0.1%
Placebo	1.4%	0.6%	0.2%	0.1%	2.4%	0.2%
Ejaculation disorder	1.4%	0.5%	0.5%	0.1%	0.3%	0.1%
Dutasteride	1.4%	0.5%	0.5%	0.1%	0.3%	0.1%
Placebo	0.5%	0.3%	0.1%	0.0%	1.2%	0.3%
Breast disorders +	0.5%	0.8%	1.1%	0.6%	1.8%	0.7%
Dutasteride	0.5%	0.8%	1.1%	0.6%	1.8%	0.7%
Placebo	0.2%	0.3%	0.3%	0.1%	1.3%	0.9%

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.

* *

All subjects switched to open-label dutasteride for months 25 to 48.

The relationship between long-term use of Dutasteride and Leydig cell tumours of the testis, Hepatocellular adenomas, and the Gleason score (grade of malignancy) of prostate cancer in patients taking long term Alpha reductase inhibitors is currently unknown. In postmarketing experience with AVODART(tm), adverse events related to allergic reactions, including rash, pruritus, urticaria, localized edema and angioedema, have been reported very rarely.

Combination with Alpha-Blocker Therapy (CombAT) study:

The CombAT study is an ongoing 4-year multicenter, double-blind study in which 4844 male subjects with BPH are randomized to receive combination therapy (AVODART(tm) 0.5 mg/day plus tamsulosin 0.4 mg/day, n =1610), AVODART(tm) alone (n =1623) or tamsulosin alone (n=1611). Adverse reaction information up to 2 years of treatment are summarized below; information for years 2 to 4 is not yet available as the study is ongoing. The most common adverse reactions reported in subjects receiving combination therapy (AVODART(tm) plus tamsulosin) were ejaculation disorders, impotence, decreased libido, breast disorders (including breast enlargement and tenderness) and dizziness. Over 2 years of treatment, drug-related ejaculation disorders occurred more frequently in subjects receiving combination therapy (9%) compared to AVODART(tm) monotherapy (2%) or tamsulosin monotherapy (3%). Over the first 2 years of treatment, study withdrawal due to adverse reactions occurred in 5% of subjects receiving combination therapy (AVODART(tm) plus tamsulosin), 3% of subjects receiving AVODART(tm) monotherapy, and 3% of subjects receiving tamsulosin monotherapy. The most common adverse reaction leading to study withdrawal in subjects receiving combination therapy was impotence (1%).

Table 2 Adverse Reactions Reported Over a 24-Month Period in >= 1% of Subjects in Any Treatment Group (CombAT)

Adverse Reactions Combination * AVODART Tamsulosin	Adverse Reaction Onset
Adverse Reactions Combination * AVODART Tamsulosin	Month 0-6 (n =1,610) (n =1,623) (n =1,611)	Month 7-12 (n =1,524) (n =1,547) (n =1,542)	Month 13-18 (n =1,424) (n =1,457) (n =1,468)	Month 19-24 (n =1,345) (n =1,378) (n =1,363)
Impotence	5.5%	1.2%	0.8%	0.3%
Combination	5.5%	1.2%	0.8%	0.3%
AVODART	3.9%	1.2%	0.6%	0.7%
Tamsulosin	2.7%	0.8%	0.4%	0.4%
Decreased libido	4.5%	0.9%	0.4%	< 0.1%
Combination	4.5%	0.9%	0.4%	< 0.1%
AVODART	3.3%	0.6%	0.7%	0.2%
Tamsulosin	1.9%	0.6%	0.4%	0.2%
Ejaculation disorders	7.6%	1.6%	0.4%	< 0.1%
Combination	7.6%	1.6%	0.4%	< 0.1%
AVODART	1.1%	0.6%	0.1%	0.1%
Tamsulosin	2.2%	0.5%	0.4%	0.1%
Breast disorders +	1.0%	1.1%	0.7%	0.3%
Combination	1.0%	1.1%	0.7%	0.3%
AVODART	0.9%	1.0%	0.8%	0.5%
Tamsulosin	0.4%	0.4%	0.2%	0.1%
Dizziness	1.1%	0.4%	0.2%	0%
Combination	1.1%	0.4%	0.2%	0%
AVODART	0.4%	0.2%	< 0.1%	< 0.1%
Tamsulosin	0.9%	0.5%	0.3%	0.1%

* Combination = AVODART 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

Includes breast tenderness and breast enlargement.

DRUG INTERACTIONS

Care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin. Based on the in vitro data, blood concentrations of dutasteride may increase in the presence of 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 1000 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.

Digoxin:

In a study of 20 healthy volunteers, AVODART(tm) did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.

Warfarin:

0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin.

Alpha-Adrenergic Blocking Agents:

In a single sequence, crossover study in healthy volunteers, the administration of tamsulosin or terazosin in combination with AVODART(tm) had no effect on the steady state pharmacokinetics of either alpha adrenergic blocker. The percent change in DHT concentrations was similar for AVODART(tm) alone compared with the combination treatment.

A clinical trial was conducted in which dutasteride and tamsulosin were administered concomitantly for 24 weeks followed by 12 weeks of treatment with either the dutasteride and tamsulosin combination or dutasteride monotherapy. Results from the second phase of the trial revealed no excess of serious adverse events or discontinuations due to adverse events in the combination group compared to the dutasteride monotherapy group. If AVODART(tm) is administered in combination with the alpha-blocker tamsulosin, please refer to the ADVERSE REACTIONS and CLINICAL TRIALS sections of this Product Monograph.

Calcium Channel Antagonists:

In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when co-administered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was co administered with dutasteride (+7%, n = 4).

The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended.

Cholestyramine:

Administration of a single 5 mg dose of AVODART(tm) followed 1 hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.

Other Concomitant Therapy:

Although specific interaction studies were not performed with other compounds, approximately 90% of the subjects in the 3 Phase III pivotal efficacy studies receiving AVODART(tm) were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of AVODART(tm) and concurrent therapy when AVODART(tm) was co-administered with anti-hyperlipidemics, angiotensin converting enzyme (ACE) inhibitors, beta adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.

Dutasteride absorption is not affected by food. The effects of CYP3A4 inhibitors found in foods on dutasteride pharmacokinetics have not been studied. Care should be taken when administering dutasteride to patients who chronically consume CYP3A4 inhibitors found in foods and beverages such as grapefruit juice.

The effects of herbal remedies on the pharmacokinetics of dutasteride have not been studied. Care should be taken when administering dutasteride to patients who chronically consume herbal remedies containing CYP3A4 inhibitors (e.g., milk thistle) or CYP3A4 inducers (e.g., St. John's wort).

Effects on Prostate Specific Antigen: PSA levels generally decrease in patients treated with AVODART(tm) as the prostate volume decreases. In approximately one-half of the subjects, a 20% decrease in PSA is seen within the first month of therapy. After 6 months of therapy, PSA levels stabilize to a new baseline that is approximately 50% of the pre- treatment value. Results of subjects treated with AVODART(tm) for up to 2 years indicate this 50% reduction in PSA is maintained. Therefore, a new baseline PSA concentration should be established after 3 to 6 months of treatment with AVODART(tm) (see WARNINGS AND PRECAUTIONS: Effects on PSA and Prostate Cancer Detection).

DOSAGE AND ADMINISTRATION

Adult males (including elderly)

The recommended dose of AVODART(tm) (dutasteride) soft gelatin capsules is one 0.5 mg capsule taken orally once a day.

AVODART(tm) 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(tm) may be taken with or without food. (see WARNINGS AND PRECAUTIONS, Exposure of Women - Risk to Male Fetus and SPECIAL HANDLING INSTRUCTIONS).

Renal Impairment

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady state 0.5 mg dose of dutasteride is recovered in human urine, and no adjustment in dose is anticipated for patients with renal impairment.

Hepatic Impairment

If a dose is missed the tablet can be taken at the next scheduled dose. Extra capsules taken for missed doses are not necessary.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

In volunteer studies of AVODART(tm) (dutasteride) soft gelatin capsules, single daily doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to 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 AVODART(tm). Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride in consideration.

ACTION AND CLINICAL PHARMACOLOGY

Dutasteride, a synthetic 4-azasteriod compound, inhibits the conversion of testosterone to 5 a-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 a-reductase, which exists as 2 isoforms, Type I and Type II. Both Type I and Type II isoenzymes are present in the prostate. The Type I isoenzyme is also responsible for testosterone conversion in the skin and liver. It has been observed that compared to normal tissue, the expression of both isoenzymes are increased in BPH tissue. Dutasteride is a competitive and specific inhibitor of both Type I and Type II 5 a-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

The maximum effect of daily doses of dutasteride on the reduction on DHT is dose dependent and is observed within 1-2 weeks. After 1 week and 2 weeks of daily dosing of dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90% respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years. The testosterone concentrations remain within the physiological normal range. In BPH patients treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, p < 0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, p < 0.001). In BPH patients (N=43) treated with dutasteride 0.5 mg/day or placebo for 3 months prior to transurethral resection of the prostate (TURP), the adjusted mean intraprostatic DHT level was significantly lower in the dutasteride group compared to the placebo group (0.209 ng/g and 3.23 ng/g, respectively, p<0.001). In another study, men with localized prostate cancer received a loading dose of dutasteride 10 mg/day for 7 days followed by dutasteride 5 mg/day for up to 10 weeks prior to radical prostatectomy, Mean DHT concentrations in prostatic tissue were substantially lower in the dutasteride group compared with placebo (177 and 6,179 pg/g, respectively).

Absorption:

Dutasteride is rapidly absorbed with peak concentrations occurring at 1 to 3 hours and absorption is not affected by food. Absolute bioavailability is approximate 60% relative to a 2-hour intravenous infusion.

Distribution:

Dutasteride has a large volume of distribution (300-500 L) and is highly bound to proteins in plasma (> 99.5%). The half-life of dutasteride is 3 to 5 weeks. Steady state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing with dutasteride 0.5 mg once daily. Similarly, dutasteride concentrations in semen reached steady-state at 6 months. After 52 weeks of treatment, semen dutasteride concentrations averaged 3.4 ng/mL (range 0.4 to 14 ng/mL).

Metabolism:

Dutasteride is extensively metabolized in humans. Studies showed that CYP3A4 isoenzymes are involved in metabolism of dutasteride.

Excretion:

Dutasteride and its metabolites were excreted mainly in feces. Only trace amounts of unchanged dutasteride were found in urine (< 1%) (see DETAILED PHARMACOLOGY).

Geriatrics:

No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5 mg dose of dutasteride. In this single-dose study, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal studies, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender:

AVODART(tm) is not indicated for use in women (see WARNINGS AND PRECAUTIONS).

Race:

Hepatic Insufficiency:

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied.

Renal Insufficiency:

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

STORAGE AND STABILITY

SPECIAL HANDLING INSTRUCTIONS

Dutasteride is absorbed through the skin; therefore, women and children must avoid contact with leaking capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).

DOSAGE FORMS, COMPOSITION AND PACKAGING

AVODART(tm) (dutasteride) soft gelatin capsules are opaque, yellow, oblong-shaped, soft gelatin capsules imprinted with GXCE2 in red ink on one side. Available in blister packages of 30 capsules. Each soft gelatin capsule for oral administration contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The following non-medicinal ingredients are contained in the capsule shell: glycerol, gelatin (from certified, BSE-free, nonporcine sources), titanium dioxide, medium chain triglycerides, lecithin and iron oxide yellow. The soft gelatin capsules are printed with edible red ink containing iron oxide red as the colourant.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: dutasteride Chemical name: (5 alpha, 17 beta)-N-{2,5-bis(trifluoromethyl)phenyl}- 3-oxo -4-azaandrost-1- ene-17- carboxamide Molecular formula and molecular mass: C27H30F6N2O2 , 528.5 Structural formula: Physicochemical properties: Dutasteride is a white to pale yellow powder with a melting point of 242 to 250degC. 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.

CLINICAL TRIALS

Study demographics and trial design

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%).

Study results

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. Pooled results of the 3 pivotal studies compared to placebo at Month 6 showed that dutasteride was associated with a significantly greater change from baseline (p < 0.001). 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 18, the mean decrease from baseline was -3.7 units for dutasteride and -2.1 units for placebo with a mean difference of -1.6 (range, -1.4 to -1.9 units in each of the 3 studies, p < 0.001). 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). Continued symptom improvement was also seen during the additional 2 years of open label extension studies. For those subjects who continued with dutasteride treatment the change in AUA-SI score from months 24 to 48 was statistically significant (p < 0.001). The mean decrease from baseline in AUA-SI symptom scores across the 3 studies pooled at Month 48 was -6.5 units for subjects on continued dutasteride treatment throughout 48 months and -5.6 units for subjects on placebo treatment for 24 months followed by dutasteride treatment for 24 months (See Figure 2). 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. Figure 1 represents the 24 month pooled phase III data for AUA-SI. Figure 2 represents the 48 months intent to treat population. At the 2 year timepoint, all continuing subjects switched to open-label dutasteride.

Figure 1. AUA-SI Score * Change from Baseline (Pivotal Studies Pooled)

Figure 2. AUA-SI * Score Mean Change from Baseline (Open-Label ITT * * Population, Pooled Data)

AUA SI (American Urological Association Symptom Index) is a seven-item questionnaire with a maximum score of 35. Entry criteria included a screening score of >=12 (moderate to severe symptoms). A reduction in score signifies an improvement in symptoms.

Qmax (maximum urine flow) 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 18, the mean increase in Qmax was 1.7 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.0 mL/sec (range, 0.8 to 1.1 units 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 3). The increase in maximum urine flow rate was continued during the additional 2 years of open label extension studies. For those subjects who continued with dutasteride treatment the mean increase in Qmax from months 24 to 48 was statistically significant (p <= 0.007). The mean increase from baseline in maximum urinary flow rate across the 3 studies pooled at Month 48 was 2.7 ml/sec for subjects on continued dutasteride treatment throughout 48 months and 1.9 ml/sec for subjects on placebo treatment for 24 months followed by dutasteride treatment for 24 months (See Figure 4).

Figure 3. Qmax Change from Baseline (Pivotal Studies Pooled)

Figure 4. Qmax (mL/sec) Mean Change from Baseline (Open-Label ITT Population, Pooled Data)

Acute Urinary Retention and Surgical Intervention

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 (BPH-SI). Compared with placebo, AVODART(tm) was associated with a statistically significantly lower incidence of AUR (1.8% for AVODART(tm) 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(tm) vs. 4.1% for placebo, p < 0.001; 48% reduction in risk, 95% CI: [26-63%]) (See Figures 5a and 6a). The pooled incidence of AUR on dutasteride treatment was low during the 24-month open-label phase (Months 24-48) with an incidence of 1.9% for the previous placebo group (P/D group) and 1.2% for the previous dutasteride group (D/D group). Compared with the P/D group, the D/D group had reduced the risk of AUR by 40%, but the reduction was not statistically significant (See Figure 5b). The pooled incidence of BPH-related surgery on dutasteride treatment was low during the 24-month open-label phase (Months 24-48) with an incidence of 0.8% for both the previous placebo group (P/D group) and for the previous dutasteride group (D/D group) (See Figure 6b). In addition, a listing of the BPH- related surgical interventions can be found in Table 3.

Figure 5a. Percent of Subjects Developing Acute Urinary Retention Over a 24 Month Period (Pivotal Studies Pooled)

Figure 5b. Percent of Subjects Developing Acute Urinary Retention Over a 48 Month Period (Pivotal Studies Pooled)

Figure 6a. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 24 Month Period (Pivotal Studies Pooled)

Figure 6b. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 48 Month Period (Pivotal Studies Pooled)

Table 3. Surgical interventions over a 48 month period (Double Blind and Open-Label ITT * population)

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 7). 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. The mean percent change from baseline in prostate volume across the 3 studies pooled at Month 48 was -27.3% for subjects on continued dutasteride treatment throughout 48 months and -21.7% for subjects on placebo treatment throughout 24 months followed by dutasteride treatment for 24 months (see Figure 8).

Figure 7. Prostate Volume Percent Change from Baseline (Pivotal Studies Pooled)

Figure 8. Prostate Volume Mean Percent Change from Baseline (Double Blind and Open-Label ITT Population, Pooled Data)

Summary of Clinical Studies: Data from 3 large, well controlled efficacy studies demonstrate that treatment with AVODART(tm) (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(tm) arrests the disease process of BPH in men with an enlarged prostate.

AVODART(tm) was used in combination with tamsulosin, an alpha1-adrenergic blocking agent, for up to 36 weeks in a multicentre double blind parallel group study involving 327 patients. After 24 weeks of combination therapy approximately 50% of patients had tamsulosin withdrawn. Seventy-seven percent of patients who continued with AVODART(tm) monotherapy felt the same or better 6 weeks after withdrawal of tamsulosin and 93% of these patients had sustained symptom control 12 weeks after withdrawal. Maintenance of symptom control was proportionally slightly higher in patients who continued on combination therapy (91% Vs 77% at Week 30). Both regimens were well tolerated (see PRECAUTIONS, Drug Interactions).

The CombAT study is an ongoing 4-year multicenter, double-blind study in which 4844 men are randomized to receive combination therapy (AVODART(tm) 0.5 mg/day plus tamsulosin 0.4 mg/day, n=1610), AVODART(tm) alone (n = 1623) or tamsulosin alone (n=1611). The 2-year primary endpoint is change in International Prostate Symptom Score (IPSS) and 4-year primary endpoint is reduction in risk of AUR or BPH- related surgery. At year 2, the mean change from baseline (+- SD) in IPSS was -6.2 (+-7.14) for combination therapy, -4.9 (+-6.81) for AVODART(tm) alone, and -4.3 (+-7.01) for tamsulosin alone, with a mean difference between combination therapy and AVODART(tm) alone of -1.3 units (p<0.001), and between combination therapy and tamsulosin alone of -1.8 units (p<0.001). The study is ongoing and results on BPH progression/outcome events are pending upon completion of the 4-year CombAT study (see Figure 9).

Figure 9. International Prostate Symptom Score Change from Baseline (CombAT study)

DETAILED PHARMACOLOGY

Dutasteride is administered orally as a solution in soft gelatin capsules. Following oral administration of a single 0.5 mg dutasteride soft capsule, the time to peak serum concentrations of dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60% relative to a 2-hour intravenous infusion. The bioavailability of dutasteride is not affected by food. Dutasteride has a large volume of distribution (300 to 500 L) and is highly bound to plasma proteins (> 99.5%). Following daily dosing, dutasteride serum concentrations achieve 65% of steady state concentration after 1 month and approximately 90% after 3 months. Steady state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Similarly to serum, dutasteride concentrations in semen achieved steady state at 6 months. After 52 weeks of therapy, semen dutasteride concentrations averaged 3.4 ng/mL (range 0.4 to 14 ng/mL). Dutasteride partitioning from serum into semen averaged 11.5%.

, dutasteride is metabolized by the human cytochrome P450 enzyme CYP3A4 to two minor monohydroxylated metabolites, but is not metabolized by CYP1A2, CYP2C9, CYP2C19 or CYP2D6. In human serum, following dosing to steady state, unchanged dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and

6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The five human serum metabolites of dutasteride have been detected in rat serum, however the stereochemistry of the hydroxyl additions at the 6 and 15 positions in the human and rat metabolites is not known. Dutasteride is extensively metabolized in humans. Following oral dosing of dutasteride 0.5 mg/day to steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine. At therapeutic concentrations, the terminal half-life of dutasteride is 3 to 5 weeks. Serum DHT concentrations which correlate to clinical effect, return to baseline (no clinical effect) within approximately 4 months after discontinuation of treatment. Dutasteride pharmacokinetics can be described as first order absorption process and two parallel elimination pathways, one saturable (concentration dependent) and one non- saturable (concentration independent). At low serum concentrations (less than 3 ng/mL), dutasteride is cleared rapidly by both the concentration dependent and concentration independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days. At serum concentrations greater than 3 ng/mL, dutasteride is cleared slowly by linear elimination with a half-life of 3 to 5 weeks. At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower clearance dominates and the total clearance is linear and concentration independent. Dose proportionality analysis across doses (0.5 mg - 5.0 mg) on Day 1 and Day 28 indicated that the pharmacokinetics of dutasteride were dose independent.

TOXICOLOGY

Acute Toxicology

In acute oral toxicity studies, the maximum non-lethal dose (MNLD) was > 2,000 mg/kg in mice and >1,500 mg/kg in rats, which is 200,000 and 150,000 times greater, respectively, than the proposed therapeutic dose of 0.01 mg/kg (0.5 mg/day assuming a 50 kg person). Intraperitoneal administration resulted in acute polyserositis due to the irritant properties of the vehicle (PEG 400 with 0.1% w/v Tween 80) and this was exacerbated by the presence of dutasteride, due to the physical properties of the compound. An intraperitoneal MNLD was therefore not identified in either species. Acute oral and intraperitoneal administration of dutasteride to mice and rats produced no evidence of unequivocal target organ toxicity. Reduction in the size of the prostate and seminal vesicles with accompanying microscopic changes were noted predominantly in treated males and are consistent with a reduction in dihydrotestosterone (DHT) levels due to the pharmacological activity of dutasteride as a 5 a-reductase (5AR) inhibitor.

Long Term Toxicity

Repeat oral dose toxicity studies were conducted in rats for 5 and 26 weeks (up to 500 mg/kg/day in males and 100 or 30 mg/kg/day, respectively, in females) and in dogs for 26 and 53 weeks (up to 50 or 10 mg/kg/day, respectively, in males and females). The main findings consisted of changes in the male and female reproductive organs in both species and changes in the thyroid and other endocrine organs in dogs. These effects appear to be compatible with physiological changes in steroidogenic tissues and changes in the hypothalamic/pituitary/gonadal axis, which is typical of 5AR inhibition with subsequent decrease in DHT levels. Treatment-related findings seen in male reproductive organs included decrease in size and related histopathological changes in the prostate of rats and dogs, epithelial atrophy and decreased secretion of the seminal vesicles in rats, decreased epididymis weight in the rat and histopathological changes consistent with atrophy in the epididymis in dogs. Effects on the testis were limited to an increase in testis weight in rats following dosing for 5 weeks. There were no significant changes in spermatogenesis in the rat or dog. Treatment-related findings seen in female reproductive organs included decreased ovary and uterus/cervix weights, increased incidence of dioestrus or increased occurrence of ovarian (follicular) cysts in rats, and microscopic changes in the uterus and shifts in the oestrus cycle to the luteal phase in dogs. In dogs, there were changes in the thyroid consisting of a reversible increase in thyroid weight, with correlating microscopic changes of reduced colloid content and C-cell hyperplasia in the 26 week study and vacuolated follicular cells in the 53 week study. Other reversible changes in endocrine organs consisted of slight enlargement of chromophobes in the pars distalis of the pituitary and hypertrophy, cytoplasmic vacuolation and increased lipofuscin-like pigment in the adrenal cortex. Clinical signs indicative of a non-specific, reversible centrally mediated toxicity were seen in some animals following repeat dosing. This was not associated with histopathological changes and occurred at exposures 425-fold in rats and 315-fold in dogs the clinical serum concentration at steady state (40 ng/mL). Due to the expected dutasteride-related effects as a result of 5AR inhibition, it was not possible to establish no-observed-adverse-effect-level (NOAEL) in the repeat dose studies. However, in the 26 week rat and 53 week dog studies, there were no other toxicologically significant effects in female rats at up to 84-fold the clinical exposure of 40 ng/mL, in male rats at up to 17-fold the clinical exposure, in females dogs at up to 203-fold the clinical exposure or in male dogs at up to 117-fold the clinical exposure.

Special Toxicity

Acute dermal application of dutasteride in rabbits caused slight but reversible irritancy. The estimated dermal LD50 of dutasteride in rabbits is > 2,000 mg/kg. In an acute dermal absorption study in rabbits at doses of 0.1 to 40 mg/kg, dutasteride was detected in the serum. Slight to moderate dermal irritancy was observed in treated and control groups. However, additional findings (including subcutaneous hemorrhaging) predominately in treated animals and macroscopic observations (multiple red areas in the skin) in animals at 40 mg/kg suggest that dutasteride is a dermal irritant. Acute ocular application of dutasteride in rabbits caused slight iridial irritation and slight to moderate conjunctival irritation, which were reversible within 72 h. Dermal application of dutasteride in guinea pigs demonstrated no sensitizing effect.

, dutasteride (0.0111 mg/mL) did not increase haemolysis or the level of free haemoglobin in human erythrocytes and did not increase protein flocculation, turbidity or precipitation in human plasma. Both dutasteride (0.0111 mg/mL) and the vehicle control (a complexing agent) produced minimal evidence of perivascular irritation in mice. Dutasteride produced no intravenous irritation in rabbits.

Reproduction and Teratology

In a fertility study, male rats orally administered dutasteride (0.05 to 500 mg/kg/day) for up to 31 weeks showed reversible dose- and time-dependent decreases in fertility, reductions in the weights of seminal vesicles, prostate and epididymides and microscopic changes in these male reproductive organs. The effects are consistent with the pharmacological activity of dutasteride. No effects were noted in the testis, and sperm concentration and motility were unaffected by treatment. The decrease in fertility with dutasteride is likely to be related to a failure of copulatory plug formation as a consequence of the decreased weight of the seminal vesicles and prostate. As such a mechanism is not thought to be relevant to species that do not form copulatory plugs, this finding is considered to be of no clinical concern. Furthermore, the decreased fertility in the rat was not associated with an effect on spermatogenesis. In an oral fertility study in female rats, the NOAEL for the F0 generation was 0.05 mg/kg/day. Fetal body weight was reduced at all dosages of dutasteride (0.05 to 30 mg/kg/day) and feminisation of male fetuses occurred at >= 2.5 mg/kg/day. In an oral embryofetal development study in rats, the NOAEL for the F0 generation was 0.05 mg/kg/day. Fetal body weight was reduced at >= 2.5 mg/kg/day and feminisation of male fetuses and F1 male pups occurred at all dosages of dutasteride (0.05 to 30 mg/kg/day). Increased incidences of skeletal variations considered to be reversible delays in ossification associated with reduced body weight were noted at 12.5 and 30 mg/kg/day. In a rabbit oral embryofetal development study, the NOAEL for the F0 generation was 200 mg/kg/day. Dutasteride produced feminisation of male fetuses at all dosages (30 to 200 mg/kg/day). Fusion of the jugal and zygomal bones was noted in a minority of fetuses at all dosages, but it is uncertain whether this was unequivocally related to treatment. In a further rabbit study, oral dosing at 0.05 to 30 mg/kg/day also produced feminisation of male fetuses at all dosages. Feminisation of male fetuses is an expected effect of the pharmacological activity of dutasteride, which as a 5AR inhibitor inhibits the conversion of testosterone to DHT. In the male rat fertility study, low levels of dutasteride were detected in the serum of untreated female rats mated to treated males and, in humans, dutasteride was detected in semen at a maximum concentration of 14.0 ng/mL following repeated oral dosing for 12 months. To determine the effects of dutasteride on embryo-fetal development of male fetuses, an intravenous embryofetal development study was conducted in the rhesus monkey. Intravenous administration of dutasteride at doses up to 2010 ng/animal/day during embryofetal development did not produce adverse maternal toxicity, fetal toxicity or feminisation of male offspring. The high dose represents at least a 186-fold multiple of the potential maximum daily dose from 5mL semen from a man treated with dutasteride at 0.5 mg/day (assuming 100% absorption), for a 50 kg woman. Dutasteride is highly bound to proteins in human semen (> 96%), potentially reducing the amount of dutasteride available for vaginal absorption. In an oral pre- and -post natal rat study, the NOAEL for the F0 generation was 0.05 mg/kg/day. Earlier onset of vaginal patency was noted in F1 females at 2.5, 12.5 and 30 mg/kg/day. Feminisation (decreased anogenital distance) was noted at all dosages (0.05 to 30 mg/kg/day) in F1 males. At >= 2.5 mg/kg/day, F1 males had increased incidences of hypospadia resulting in decreased fertility and increased occurrence of inflammation of the genitourinary tract and prostatitis. Prostate and seminal vesicle weights were reduced at >= 2.5 mg/kg/day in F1 males. These changes are expected effects of the pharmacological activity of dutasteride.

Mutagenicity

Dutasteride and the 4'-hydroxy metabolite of dutasteride, showed no evidence of mutagenic activity in the Ames test at concentrations up to 5,000 mg/plate in the presence or absence of S9 metabolic activation. Similarly, the 1,2-dihydro metabolite of dutasteride, demonstrated no mutagenic activity in a miniwell Ames test at concentrations up to 800 mg/well in the presence or absence of S9 metabolic activation. Dutasteride did not show any evidence of clastogenic activity in vitro in Chinese Hamster Ovary cells at concentrations up to 1,150 mg/mL or in vivo in rat micronucleus tests at dose levels of up to 1,500 mg/kg/day for 6 days.

Carcinogenicity

A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290 fold the expected clinical exposure to a 0.5 mg daily dose) in females only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day for males and 0.8, 6.3, and 15 mg/kg/day for females, there was an increase in Leydig cell adenomas in the testes at 53 mg/kg/day (135-fold the expected clinical exposure). An increased incidence of Leydig cell hyperplasia was present at 7.5 mg/kg/day (52-fold the expected clinical exposure) and 53 mg/kg/day in male rats. A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5a-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5a-reductase inhibition. At tumorigenic doses in rats, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure.

REFERENCES

Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol 1999 Mar; 68(5-6):189-95. Roehrborn CG, Lukkarinen O, Mark S, Siami P, Ramsdell J, Zinner N. Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies. BJU Int 2005 Sep; 96(4):572-7. Roehrborn CG, Marks LS, Fenter T, Freedman S, Tuttle J, Gittleman M, et al. Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 2004; 63 (4), 2004; 709-715. Stuart JD, Lee FW, Simpson ND, Kadwell SH, Overton LK, Hoffman CR et al. Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5 alpha-reductases: determinants for different in vivo activities of GI198745 and finasteride in the rat. Biochem Pharmacol 2001; 62(7):933-942. Thomas LN, Lazier CB, Gupta R, Norman RW, Troyer DA, O'Brien SP, et al. Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 2005 May 15; 63(3): 231-9. IMPORTANT: PLEASE READ

This leaflet is part III of a three-part "Product Monograph" published when AVODART(tm) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about AVODART(tm). Contact your doctor or pharmacist if you have any questions about the drug.

AVODART(tm) is used in the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with enlarged prostates.

BPH is a non-cancerous enlargement of the prostate gland, which is located at the lower portion of the urinary bladder surrounding the urethra (urine carrying tube). In men with BPH, the prostate gland becomes large enough to squeeze the urine tube running through it. If the urine tube is squeezed it narrows, making it more difficult with urination resulting in some or all of the following symptoms:

As the disease progresses, untreated BPH can lead to an increased risk of complete blockage of urine flow (acute urinary retention) and/or the need for surgery.

There are three main options for treating BPH. You and your doctor should decide which option is best for you after

If you have an enlarged prostate but your BPH symptoms are not particularly bothersome, your doctor may recommend regular check-ups to monitor your symptoms and no other treatment at this time.

If your symptoms are too bothersome for you, your doctor may recommend treatment with a medicine to relax smooth muscle in the prostate and/or a medicine to decrease prostate size.

AVODART(tm) belongs to a group of medicines called 5 alpha- reductase enzyme inhibitors. AVODART(tm) works to lower the

production of dihydrotestosterone (DHT) in the body, leading to reduced prostate size, improved urinary flow, reduced risk of

BPH related surgery. While some men have fewer problems and symptoms after 3 months of treatment with AVODART(tm), a treatment period of at least 6 months is usually necessary to see if AVODART(tm) will work for you.

Non medicinal ingredients in your medicine include butylated hydroxytoluene, gelatin, glycerol, iron oxide yellow, lecithin,

caprylic/capric acid, purified water, titanium dioxide, and red printing ink containing iron oxide red as the colourant.

Men treated with AVODART(tm) should not donate blood until at least 6 months after their final dose in order to prevent giving AVODART(tm) to a pregnant woman through blood transfusion.

Before taking AVODART(tm) tell your doctor if you have or have had liver problems or cancer of the prostate.

BPH and not for cancer. But a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These checks should continue while you take AVODART(tm).

Your physician may have done a blood test called PSA. AVODART(tm) can alter PSA values. AVODART(tm) does

lower your PSA test result by about 50%. This low PSA Level may give you a false sense of security. Keep a written record

you have been taking AVODART(tm) for the exact number of months you have used. For more information, talk to your physician.

Prior to treatment with AVODART(tm), you should have a thorough urological evaluation to determine the severity of your condition, and to exclude the need for immediate surgery or the possibility of prostate cancer. A thorough urological examination generally includes a digital rectal examination (DRE) and an evaluation of urinary symptoms. Your physician may also obtain a blood test for prostate specific antigen (PSA) (see About Prostate Specific Antigen).

You must have a regular checkup by your doctor while taking AVODART(tm), including digital rectal examination and PSA determination.

If you accidentally take too many capsules, ask your doctor what to do or contact your nearest hospital emergency

If you miss a dose, you can just take the next scheduled dose. Don't take any extra capsules to make up for doses you forgot

The most common side effects of AVODART(tm) are impotence (not able to achieve or maintain an erection), decrease in libido (decreased desire to have sex or a reduced sex drive), changes or problems with ejaculations (including a decrease in amount of semen released during sex) and breast swelling or tenderness.

Make sure your doctor knows what other medicines you are taking, or have recently taken. Remember to include all

vitamins, iron or calcium, which you have bought yourself. Please inform your doctor about regular consumption of grapefruit juice. This drink is known to increase the blood levels of some drugs in the body.

AVODART(tm) can alter the results of a prostate specific antigen (PSA) test. AVODART(tm) can lower your prostate specific antigen (PSA) test result by about 50%.

If you notice these side effects and any other side effects not mentioned in this leaflet, tell your doctor or pharmacist.

This is not a complete list of side effects. For any unexpected effects while taking AVODART(tm), contact your doctor or pharmacist.

Swallow the capsule whole. Do not chew or open the capsules. Contact with the contents of the capsules may make your mouth or throat sore.

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.7333 Mississauga Road

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Capsules, 0.5 mg	gelatin For a complete listing see Dosage Forms, Composition and Packaging section.

First BPH surgical Intervention	Double blind		Open label
	Placebo	Dutasteride	Placebo/ Dutasteride	Dutasteride/ Dutasteride
	n=2158	n=2167	n=1152	n=1188
	# (%)	# (%)	# (%)	# (%)
TURP * *	65 (3.01)	26 (1.20)	2 (0.17)	3 (0.25)
Transurethral resection	4 (0.19)	7 (0.32)	0 (0)	0 (0)
Prostactectomy, laser	3 (0.14)	2 (0.09)	0 (0)	0 (0)
Prostactectomy	3 (0.14)	3 (0.14)	0 (0)	0 (0)
TUMT * * *	2 (0.09)	2 (0.09)	3 (0.26)	3 (0.25)
Thermotherapy	0 (0)	2 (0.09)	0 (0)	0 (0)
Electrorecsection, prostate	2 (0.09)	0 (0)	1 (0.09)	0 (0)
Prostactectomy, open	2 (0.09)	0 (0)	1 (0.09)	0 (0)
Prostactectomy, retropubic	2 (0.09)	0 (0)	0 (0)	0 (0)
Prostactectomy, transvesical	1 (0.05)	1 (0.05)	0 (0)	0 (0)
Adenectomy, prostate	1 (0.05)	0 (0)	0 (0)	0 (0)
Prostactectomy, suprapubic	0 (0)	1 (0.05)	0 (0)	0 (0)
Prostactectomy, partial	0 (0)	0 (0)	1 (0.09)	0 (0)
Adenectomy	0 (0)	1 (0.05)	0 (0)	0 (0)
Hyperthermia, microwave	0 (0)	0 (0)	0 (0)	1 (0.08)
Other	4 (0.19)	2 (0.09)	1 (0.09)	1 (0.08)

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect		Talk with your doctor or pharmacist		Stop taking drug and call your doctor or pharmacist
Symptom / effect		Only if severe	In all cases	Stop taking drug and call your doctor or pharmacist
Rare	Sudden wheeziness or chest tightness			9
	Swelling of eyelids, face or lips			9
	Lumpy skin rash or "hives" anywhere on the body			9

Date of Revision: August 22, 2008

Control Number: 116603

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 16

PART III: CONSUMER INFORMATION. 37

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions AVODARTTM is for use for men only.

Exposure of Women-Risk to Male Fetus:

Hormone Levels

Exposure of Women-Risk to Male Fetus:

Nursing Women:

Pediatrics

Geriatrics

Effects on Prostate Specific Antigen (PSA) and Prostate Cancer Detection

ADVERSE REACTIONS

Dutasteride Monotherapy

Combination with Alpha-Blocker Therapy (CombAT) study:

DRUG INTERACTIONS

Digoxin:

Warfarin:

Alpha-Adrenergic Blocking Agents:

Calcium Channel Antagonists:

Cholestyramine:

Other Concomitant Therapy:

DOSAGE AND ADMINISTRATION

Adult males (including elderly)

Renal Impairment

Hepatic Impairment

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Absorption:

Distribution:

Metabolism:

Excretion:

Geriatrics:

Gender:

Race:

Hepatic Insufficiency:

Renal Insufficiency:

STORAGE AND STABILITY

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

PHARMACEUTICAL INFORMATION

Drug Substance

CLINICAL TRIALS

Study demographics and trial design

Study results

Effect on Symptom Scores:

Figure 1. AUA-SI Score * Change from Baseline (Pivotal Studies Pooled)

Figure 2. AUA-SI * Score Mean Change from Baseline (Open-Label ITT * * Population, Pooled Data)

Figure 3. Qmax Change from Baseline (Pivotal Studies Pooled)

Figure 4. Qmax (mL/sec) Mean Change from Baseline (Open-Label ITT Population, Pooled Data)

Acute Urinary Retention and Surgical Intervention

Figure 5a. Percent of Subjects Developing Acute Urinary Retention Over a 24 Month Period (Pivotal Studies Pooled)

Figure 5b. Percent of Subjects Developing Acute Urinary Retention Over a 48 Month Period (Pivotal Studies Pooled)

Figure 6a. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 24 Month Period (Pivotal Studies Pooled)

Figure 6b. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 48 Month Period (Pivotal Studies Pooled)

Figure 7. Prostate Volume Percent Change from Baseline (Pivotal Studies Pooled)

Figure 8. Prostate Volume Mean Percent Change from Baseline (Double Blind and Open-Label ITT Population, Pooled Data)

Figure 9. International Prostate Symptom Score Change from Baseline (CombAT study)

DETAILED PHARMACOLOGY

TOXICOLOGY

Acute Toxicology

Long Term Toxicity

Special Toxicity

Reproduction and Teratology

Mutagenicity

Carcinogenicity

REFERENCES