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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dutasteride 0.5 mg soft capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 0.5 mg dutasteride.

For thefull list of excipients, see section 6.1.

Excipient with Known Effect: Allura red (E129)

3 PHARMACEUTICAL FORM

Capsule, soft.

Clear oily colourless solution encapsulated in yellow coloured, opaque, oblong shaped soft gelatin capsule of length 19.7 mm ± 1.5 mm and width 6.70 mm ± 1 mm with "DU" imprinted with red ink along the length of body on one side of capsule.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).

Reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate to severe symptoms of BPH.

For information on effects of treatment and patient populations studied in clinical trials please see section 5.1.

4.2 Posology and method of administration

Posology:

Adults (including elderly):

The recommended dose of Dutasteride is one 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 contents may result in irritation of the oropharyngeal mucosa. The capsules may be taken with or without food. Although an improvement may be observed at an early stage, it can take up to 6 months before a response to the treatment can be achieved. No dose adjustment is necessary in the elderly.

Renal impairment

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment (see section 5.2).

Hepatic impairment

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of dutasteride is contraindicated (see section 4.3).

Paediatric population:

Dutasteride are contraindicated in children and adolescents (see section 4.3 and 4.6)

Method of administration:

Dutasteride can be administered alone or in combination with the alpha-blocker tamsulosin (0.4mg) (see sections 4.4, 4.8 and 5.1).

4.3 Contraindications

Dutasterideis contraindicated in:

-    women and children and adolescents (see section 4.6).

-    patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, soya, peanut or any of the other excipients listed in section 6.1.

-    patients with severe hepatic impairment.

4.4 Special warnings and precautions for use

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies (see section 4.2).

Cardiac failure

In two 4-year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was higher among subjects taking the combination of Dutasteride and an alpha blocker, primarily tamsulosin, than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was low (<1%) and variable between the studies. (see section 5.1).

Effects on prostate specific antigen (PSA) and prostate cancer detection

Digital rectal examination, as well as other evaluations for prostate cancer, must be performed on patients prior to initiating therapy with Dutasteride and periodically thereafter.

Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteridecauses a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.

Patients receiving Dutasteride should have a new PSA baseline established after 6 months of treatment with Dutasteride. It is recommended to monitor PSA values regularly thereafter.Any confirmed increase from lowest PSA level while on Dutasteridemay signal the presence of prostate cancer (particularly high grade cancer) or noncompliance to therapy with Dutasteride and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5a-reductase inhibitor (see section 5.1). In the interpretation of a PSA value for a patient taking Dutasteride, previous PSA values should be sought for comparison.

Treatment with Dutasteride does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established (see section 5.1).

Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of

Dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Dutasteride therapy, no adjustment to its value appears necessary.

Prostate cancer and high grade tumours

Results of one clinical study (the REDUCE study) in men at increase risk of prostate cancer revealed a higher incidence of Gleason 8 - 10 prostate cancers in dutasteride treated mencompared to placebo. The relationship between dutasteride and high grade prostate cancer is not clear. Men taking Dutasterideshould be regularly evaluated for prostate cancer risk including PSA testing (see section 5.1).

Leaking capsules

Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules (see section 4.6). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Hepatic impairment

Dutasteride was not studied in patients with liver disease. Caution should be used in the administration of dutasteride to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).

Breast neoplasia

Breast cancer has been reported in men taking dutasteride in clinical trials (see section 5.1) and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.

This medicine contains Allura red (E129) that may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, please see section 4.4.

Effects of other drugs on the pharmacokinetics of dutasteride

Use together with CYP3A4 and/or P-glycoprotein-inhibitors:

Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients.

Long-term combination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5-alpha reductase at increased dutasteride exposure, is not likely. However, a reduction of the dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached.

Administration of 12g cholestyramine one hour after a 5mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effects of dutasteride on the pharmacokinetics of other drugs

Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2D6, CYP2C9, CYP2C19, CYP2B6 or CYP3A4.

In vitro, dutasteride is not metabolized by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.

In a small study (N=24) of two weeks duration in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study.

4.6 Fertility, pregnancy and lactation

Dutasteride is contraindicated for use by women.

Fertility

Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). The possibility of reduced male fertility cannot be excluded.

Pregnancy

As with other 5 alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving Dutasteridea day. It is not known whether a male foetus may be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride(the risk of which is greatest during the first 16 weeks of pregnancy).

As with all 5 alpha reductase inhibitors, when the patient's partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom.

For information on preclinical data, see section 5.3.

Breast-feeding

It is not known whether dutasteride is excreted in human milk.

4.7 Effects on ability to drive and use machines

Based on the pharmacodynamic properties of dutasteride, treatment with dutasteride would not be expected to interfere with the ability to drive or operate machinery.

4.8 Undesirable effects

DUTASTERIDE AS MONOTHERAPY

Approximately 19% of the 2167 patients who received dutasteride in the 2 year Phase III placebo-controlled trials developed adverse reactions during the first year of treatment. The majority of events were mild to moderate and occurred in the reproductive system. No change to the adverse event profile was apparent over a further 2 years in open-label extension studies.

The following table shows adverse reactions from controlled clinical trials and postmarketing experience. The listed adverse events from clinical trials are investigator-judged drug-related events (with incidence more than or equal to 1%) reported with a higher incidence in patients treated with dutasteride compared with placebo during the first year of treatment. Adverse events from post-marketing experience were identified from spontaneous post-marketing reports; therefore the true incidence is unknown:

Very common ( 1/10); Common (> 1/100, 1/10); Uncommon (> 1/1,000, < 1/100); Rare ( 1/10,000, > 1 /1,000); Very rare (< 1/10,000); not known (cannot be estimated from the available data).

Organ system	Adverse reaction	Incidence from clinical trial data
		Incidence during year 1 of treatment (n=2167)	Incidence during year 2 of treatment (n=1744)
Reproductive system and breast disorders	Impotence	6.0%	1.7%
	Altered (decreased) libido*	3.7%	0.6%
	Ejaculation disorders*	1.8%	0.5%
	Breast disorders+	1.3%	1.3%
Immune system disorders	Allergic reactions including rash, pruritus, urticaria, localised oedema, and angioedema	Incidence estimated from postmarketing data
		Not known
Psychiatric disorders	Depressed mood	Not known
Skin and subcutaneous tissue disorders	Alopecia (primarily body hair loss), hypertrichosis	Uncommon
Reproductive system and breast disorders	Testicular pain and swelling	Not known

*These sexual adverse events are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse events may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown.

+ includes breast tenderness and breast enlargement

DUTASTERIDE IN COMBINATION WITH THE ALPHA-BLOCKER TAMSULOSIN

Data from the 4 year CombAT Study, comparing dutasteride 0.5mg (n=1623) and tamsulosin 0.4mg (n=1611) once daily alone and in combination (n=1610) have shown that the incidence of any investigator-judged drug-related adverse event during the first, second, third and fourth years of treatment respectively was 22%,6%, 4% and 2% for dutasteride/tamsulosin combination therapy, 15%,6%, 3% and 2% for dutasteride monotherapy and 13%,5%, 2% and 2% for tamsulosin monotherapy. The higher incidence of adverse events in the combination therapy group in the first year of treatment was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.

The following investigator-judged drug-related adverse events have been reported with an incidence of greater than or equal to 1% during the first year of treatment inthe CombAT Study; the incidence of these events during the four years of treatment is shown in the table below:

	Adverse	Incidence during treatment period
System Organ Class	Reaction	Year 1	Year 2	Year 3	Year 4
	Combinationa (n)	(n=1610)	(n=1428)	(n=1283)	(n=1200)
	Dutasteride	(n=1623)	(n=1464)	(n=1325)	(n=1200)
	Tamsulosin	(n=1611)	(n=1468)	(n=1281)	(n=1112)
Nervous	Dizziness
system disorders	Combinationa	1.4%	0.1%	<0.1%	0.2%
	Dutasteride	0.7%	0.1%	<0.1%	<0.1%
	Tamsulosin	1.3%	0.4%	<0.1%	0%
Cardiac	Cardiac failure
disorders	(composite termb)
	Combinationa	0.2%	0.4%	0.2%	0.2%
	Dutasteride	<0.1%	0.1%	<0.1%	0%
	Tamsulosin	0.1%	<0.1%	0.4%	0.2%
Reproductive	Impotence0
system and breast	Combination1	6.3%	1.8%	0.9%	0.4%
disorders,	Dutasteride	5.1%	1.6%	0.6%	0.3%
Psychiatric disorders,	Tamsulosin	3.3%	1.0%	0.6%	1.1%
Investigations	Altered (decreased)

Cardiac failure composite term comprised of Cardiac failure congestive, cardiac failure, left ventricular failure, cardiac failure acute, cardiogenic shock, left ventricular failure acute, right ventricular failure, right ventricular failure acute, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.

These sexual adverse events are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse events may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown.

Includes breast tenderness and breast enlargement.

OTHER DATA

The REDUCE study revealed a higher incidence of Gleason 8-10 prostate cancers in dutasteride treated men compared to placebo (see sections 4.4 and 5.1).Whether the effect of dutasteride to reduce prostate volume, or study related factors, impacted the results of this study has not been established.

The following has been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/ risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In volunteer studies of Dutasteride, 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 5mg 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 forDutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: testosterone-5-alpha-reductase inhibitors, ATC code: G04C B02

Dutasteride reduces circulating levels of dihydrotestosterone (DHT) by inhibiting both type 1 and type 2, 5a-reductase isoenzymes which are responsible for the conversion of testosterone to 5 a- DHT.

DUTASTERIDE AS MONOTHERAPY

Effects on DHT/Testosterone:

Effect of daily doses of Dutasterideon the reduction on DHT is dose dependant and is observed within 1-2 weeks (85% and 90% reduction, respectively).

In patients with BPH treated with dutasteride 0.5 mg/day, the median decrease in serum DHT was 94% at 1 year and 93% at 2 years and the median increase in serum testosterone was 19% at both 1 and 2 years.

Effect on Prostate Volume:

Significant reductions in prostate volume have been detected as early as one month after initiation of treatment and reductions continued through Month 24 (p<0.001). Dutasteride led to a mean reduction of total prostate volume of 23.6% (from 54.9ml at baseline to 42.1ml) at Month 12 compared with a mean reduction of 0.5% (from 54.0ml to 53.7ml) in the placebo group. Significant (p<0.001) reductions also occurred in prostate transitional zone volume as early as one month continuing through Month 24, with a mean reduction in prostate transitional zone volume of 17.8% (from 26.8ml at baseline to 21.4ml) in the Dutasteridegroup compared to a mean increase of 7.9% (from 26.8ml to 27.5ml) in the placebo group at Month 12.

The reduction of the prostate volume seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies. Reduction of the size of the prostate leads to improvement of symptoms and a decreased risk for AUR and BPH-related surgery.

CLINICAL STUDIES

Dutasteride0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms of BPH who had prostates >30ml and a PSA value within the range 1.5 - 10 ng/mL in three primary efficacy 2-year multicenter, multinational, placebo-controlled, double-blind studies. The studies then continued with an open-label extension to 4 years with all patients remaining in the study receiving dutasteride at the same 0.5 mg dose. 37% of initially placebo-randomized patients and 40% of dutasteride-randomized patients remained in the study at 4 years. The majority (71%) of the 2,340 subjects in the open-label extensions completed the 2 additional years of open-label treatment.

The most important clinical efficacy parameters were American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related surgery.

AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35. At baselinethe average score wasapprox. 17. After six months, one and two years treatment the placebo group had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Dutasteridegroup improved 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant.The improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Qmax (maximum urine flow):

Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax >15 ml/sec). After one and two years treatment the flow in the placebo group had improved by 0.8 and 0.9 ml/sec respectively and 1.7 and 2.0 ml/sec respectively in the Dutasteridegroup. The difference between the groups was statistically significant from Month 1 to Month 24.The increase in maximum urinary flow rate seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Acute Urinary Retention and Surgical Intervention

After two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the Dutasteridegroup (57% risk reduction). This difference is statistically significant and means that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of AUR.

The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the Dutasteride group (48% risk reduction). This difference is statistically significant and means that 51 patients (95% CI 33-109) need to be treated for two years to avoid one surgical intervention.

Hair distribution

The effect of dutasteride on hair distribution was not formally studied during the phase III programme, however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with male pattern hair loss (male androgenetic alopecia).

Thyroid function:

Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4 - 1.9 MCIU/mL) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not considered clinically significant. In all the clinical studies, there has been no evidence that dutasteride adversely affects thyroid function.

Breast neoplasia:

In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of registration in the 2 year open label extension, there were 2 cases of breast cancer reported in dutasteride-treated patients and 1 case in a patient who received placebo.In the 4 year CombAT and REDUCE clinical trials providing 17489 patient years exposure to dutasteride and 5027 patient years exposure to dutasteride and tamsulosin combination there were no cases of breast cancer reported in any treatment groups.

Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.

Effects on male fertility

The effects of dutasteride 0.5mg/day on semen characteristics were evaluated in healthy 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 parameters at all time points remained within the normal ranges and did not meet the 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 possibility of reduced male fertility cannot be excluded.

DUTASTERIDE COMBINATION WITH THE ALPHA-BLOCKER TAMSULOSIN

Dutasteride0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the combination of Dutasteride0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to severe symptoms of BPH who had prostates >30ml and a PSA value within the range 1.5 - 10 ng/mL in a multicentre, multinational, randomized double-blind, parallel group study (the CombAT study). Approximately 53% of subjects had previous exposure to 5-alpha reductase inhibitor or alpha-blocker treatment. The primary efficacy endpoint during the first 2 years of treatment was change in International Prostate Symptom Score (IPSS), an 8-item instrument based on AUA-SI with an additional question on quality of life. Secondary efficacy endpoints at 2 years included maximum urine flow rate (Qmax) and prostate volume.

The combination achieved significance for IPSS from Month 3 compared to Dutasteride and from Month 9 compared to tamsulosin. For Qmax combination achieved significance from Month 6 compared to both Dutasterideandtamsulosin.

The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p<0.001). Compared to Dutasteridemonotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6%(p=0.18 [95% CI -10.9% to 41.7%]).The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 5.2% for Dutasteride.

Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS deterioration by >4 points,BPH-related events of AUR, incontinence, urinary tract infection (UTI), and renal insufficiency) change in International Prostate Symptom Score (IPSS), maximum urine flow rate (Qmax) and prostate volume. Results following 4 years of treatment are presented below:

Parameter	Time-point	Combination	Dutasteride 0.5 mg soft capsules	Tamsulosin
AUR or BPH related surgery (%)	Incidence at Month 48	4.2	5.2	11.9a

Clinical progression* (%)	Month 48	12.6	17.8b	21.5a
IPSS (units)	[Baseline] Month 48 (Change from Baseline)	[16.6] -6.3	[16.4] -5.3b	[16.4] -3.8a
Qmax (mL/sec)	[Baseline] Month 48 (Change from Baseline)	[10.9] 2.4	[10.6] 2.0	[10.7] 0.7a
Prostate Volume(ml)	[Baseline] Month 48 (% Change from Baseline)	[54.7] -27.3	[54.6] -28.0	[55.8] +4.6a
Prostate Transition Zone Volume(ml)#	[Baseline] Month 48 (% Change from Baseline)	[27.7] -17.9	[30.3] -26.5	[30.5] 18.2a
BPH Impact Index (BII) (units)	[Baseline] Month 48 (Change from Baseline)	[5.3] -2.2	[5.3] -1.8b	[5.3] -1.2a
IPSS Question 8 (BPH-related Health Status) (units)	[Baseline] Month 48 (Change from Baseline)	[3.6] -1.5	[3.6] -1.3b	[3.6] -1.1a

Baseline values are mean values and changes from baseline are adjusted mean changes.

*    Clinical progression was defined as a composite of: IPSS deterioration by >4 points, BPH-related events of AUR, incontinence, UTI, and renal insufficiency.

#    Measured at selected sites (13% of randomized patients)

a.    Combination achieved significance (p<0.001) vs. tamsulosin at Month 48

b.    Combination achieved significance (p<0.001) vs. Dutasterideat Month 48

Cardiac failure:

In a 4 year BPH study of Dutasteridein combination with tamsulosinin 4844 men (the CombAT study)the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: Dutasteride, (4/1623, 0.2%) and tamsulosin, (10/1611, 0.6%).

In a separate 4-year study in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than

60 years of age) (the REDUCE study), there was a higher incidence of the composite term cardiac failure in subjects taking Dutasteride once daily (30/4105, 0.7%) compared to subjects taking placebo (16/4126, 0.4%). A post-hoc analysis of this study showed a higher incidence of the composite term cardiac failure in subjects taking Dutasterideand an alpha blocker concomitantly (12/1152, 1.0%), compared to subjects taking Dutasterideand no alpha blocker (18/2953, 0.6%), placebo and an alpha blocker (1/1399, <0.1%), or placebo and no alpha blocker (15/2727, 0.6%). (see section 4.4).

Prostate cancer and high grade tumours

In a 4-year comparison of placebo and Dutasteridein 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), 6,706 subjects had prostate needle biopsy (primarily protocol mandated) data available for analysis to determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade (Gleason 5-6, 70%).

There was a higher incidence of Gleason 8-10 prostate cancers in the Dutasteridegroup (n=29, 0.9%) compared to the placebo group (n=19, 0.6%)

(p=0.15). In Years 1-2, the number of subjects with Gleason 8-10 cancers was similar in the Dutasteridegroup (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years 3-4, more Gleason 8-10 cancers were diagnosed in the Dutasteridegroup (n=12, 0.5%) compared with the placebo group (n=1, <0.1%) (p=0.0035). There are no data available on the effect of Dutasteride beyond 4 years in men at risk of prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was consistent across study time periods (Years 1-2 and Years 3-4) in the Dutasteridegroup (0.5% in each time period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was lower during Years 3-4 than in Years 1-2 (<0.1% versus 0.5%, respectively)(see section 4.4). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).

In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for Dutasteride, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy.

The relationship between Dutasteride and high grade prostate cancer is not clear.

5.2 Pharmacokinetic properties

Absorption

Following oral administration of a single 0.5 mg dutasteride dose, the time to peak serum concentrations of dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of dutasteride is not affected by food.

Distribution

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 (C_ss) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.

Elimination

Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.

Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%)of the administered dose is excreted as unchanged 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.

The elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable.

At low serum concentrations (less than 3ng/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 therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 3-5 weeks.

Elderly

Dutasteride pharmacokinetics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5mg dose of dutasteride. No significant influence of age was seen on the exposure of dutasteride but the halflife was shorter in men under 50 years of age. Half-life was not statistically different when comparing the 50-69 year old group to the greater than 70 years old.

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, so no clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment (see section 4.2).

Hepatic impairment

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.3). Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged (see section 4.2 and section 4.4).

5.3 Preclinical safety data

Current studies of general toxicity, genotoxicity and carcinogenicity did not show any particular risk to humans.

Reproduction toxicity studies in male rats have shown a decreased weight of the prostate and seminal vesicles, decreased secretion from accessory genital glands and a reduction in fertility indices (caused by the pharmacological effect of dutasteride).

The clinical relevance of these findings is unknown.

As with other 5 alpha reductase inhibitors, feminisation of male foetuses in rats and rabbits has been noted when dutasteride was administered during gestation. Dutasteride has been found in blood from female rats after mating with dutasteride treated males. When dutasteride was administered during gestation to primates, no feminisation of male foetuses was seen at blood exposures sufficiently in excess of those likely to occur via human semen. It is not known if a male foetus will be adversely affected following seminal transfer of dutasteride.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents:

Butylated Hydroxytoluene (E321),

Mono and Diglycerides of Caprylic/capric acid

Capsule shell:

Gelatine, Glycerol,

T itanium Dioxide (E171),

Iron oxide yellow (E172 (iii)),

Printing Ink:

Allura Red AC Aluminium Lake (E129), Propylene glycol (E1520),

Hypromellose (E464) and T itanium Dioxide (E171))

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store at a temperature not exceeding 25°C

Nature and contents of container

Blisters of white opaque PVC/PVDC/Aluminium film containing 10 soft gelatin capsules packed into containers of 10, 30, 50, 60 and 90 capsules.

Not all pack sizes may be marketed.

Special precautions for disposal

Dutasteride is absorbed through the skin, 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 (see section 4.4).

Any unused product or waste material should be disposed of in accordance with local requirements.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/07/2014

DATE OF REVISION OF THE TEXT

22/11/2014