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

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

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).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Dutasteride is contraindicated in:

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

- Patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors 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).

Prostate cancer and high grade tumours

The REDUCE study, a 4-year, multicentre, randomised, double-blind, placebo controlled study investigated the effect of dutasteride 0.5 mg daily on patients with a high risk for prostate cancer (including men 50 to 75 years of age with PSA levels of 2.5 to 10 ng/ml and a negative prostate biopsy 6 months before study enrolment) compared to placebo. Results of this study revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men (n=29, 0.9%) compared to placebo (n=19, 0.6%). The relationship between dutasteride and Gleason 8 - 10 prostate cancers is not clear. Thus, men taking dutasteride should be regularly evaluated for prostate cancer (see section 5.1).

Prostate specific antigen (PSA)

Serum prostate specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteride causes 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 dutasteride may signal the presence of prostate 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 5α-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

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.

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.

Cardiovascular adverse events:

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 marginally higher among subjects taking the combination of Dutasteride and an alpha blocker, primarily tamsulosin, than it was among subjects not taking the combination However, the incidence of cardiac failure in these trials was lower in all actively treated groups compared to the placebo group, and other data available for dutasteride or alpha-blockers do not support a conclusion on increased cardiovascular risks (see section 5.1).

Breast neoplasia

There have been rare reports of male breast cancer reported in men taking dutasteride in clinical trials and during the post-marketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-alpha reductase inhibitors (see section 5.1). Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.

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).

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 12 g cholestyramine one hour after a 5 mg 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, CYP2D6, CYP2C9, CYP2C19 or CYP3A4.

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.

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 dutasteride 0.5 mg 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.

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.

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 post-marketing 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 not known:

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 post-marketing data

Not known

Psychiatric disorders

Depression

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 semen volume decreased

+ 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 in the CombAT Study; the incidence of these events during the four years of treatment is shown in the table below:

System Organ Class

Adverse Reaction

Incidence during treatment period

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 system disorders

Dizziness

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 disorders

Cardiac failure (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 system and breast disorders,

Impotencec

Combinationa

6.3%

1.8%

0.9%

0.4%

Dutasteride

5.1%

1.6%

0.6%

0.3%

Tamsulosin

3.3%

1.0%

0.6%

1.1%

Altered (decreased) libidoc

Combinationa

5.3%

0.8%

0.2%

0%

Dutasteride

3.8%

1.0%

0.2%

0%

Tamsulosin

2.5%

0.7%

0.2%

<0.1%

Ejaculation disordersc ^

Combinationa

9.0%

1.0%

0.5%

<0.1%

Dutasteride

1.5%

0.5%

0.2%

0.3%

Tamsulosin

2.7%

0.5%

0.2%

0.3%

Breast disordersd

Combinationa

2.1%

0.8%

0.9%

0.6%

Dutasteride

1.7%

1.2%

0.5%

0.7%

Tamsulosin

0.8%

0.4%

0.2%

0%

a Combination = dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

b 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.

c 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.

d Includes breast tenderness and breast enlargement.

^ Includes semen volume decreased.

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 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 national reporting system listed in Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 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 dutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.