This document has been updated since its original release. [Details]


Effective for enlarged prostate and moderate to severe symptoms

Key points

  • Dutasteride — a 5-alpha reductase inhibitor (5-ARI)
    Dutasteride is PBS listed for treating lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). Under the listing it must be prescribed with an alpha blocker, with treatment initiated by a urologist.
  • Dutasteride reduces prostate size and prevents disease progression
    Compared with placebo, dutasteride significantly reduces prostate volume, improves symptoms and urinary flow, and reduces the incidence of urinary retention and prostate surgery.
  • Alpha blockers provide rapid symptom relief
    Tamsulosin and other alpha blockers provide rapid symptom relief but do not reduce prostate size.
  • Combination therapy is more effective than an alpha blocker alone
    Dutasteride with tamsulosin is significantly more effective than tamsulosin monotherapy in reducing prostate size, improving symptoms and urinary flow, and reducing the incidence of urinary retention and prostate surgery.
  • Sexual adverse effects can occur in up to 10% of men
    Erectile dysfunction, ejaculation disorders, decreased libido, and breast tenderness and swelling can occur in up to 6% of men taking dutasteride alone and 10% of men taking dutasteride with tamsulosin.
  • Establish a new prostate-specific antigen (PSA) baseline 6–12 months after starting dutasteride
    Dutasteride decreases serum PSA levels by approximately 50% after about 6 months. Investigate sustained increases in PSA levels from the new baseline to assess adherance and prostate cancer risk.
  • Avoid donating blood until 6 months after stopping dutasteride
    Men taking dutasteride should avoid donating blood to avoid transmission to pregnant women. Dutasteride is detectable in serum for up to 4–6 months after stopping treatment.

Evidence snapshot

What is known about these drugs

Dutasteride co-administered with tamsulosin improved outcomes compared with either dutasteride or tamsulosin monotherapy in men with enlarged prostates and moderate or severe symptoms at 4 years (urinary flow: 2.4 mL/s vs 2.0 mL/s vs 0.7 mL/s, respectively; acute urinary retention: 2.2% vs 2.7% vs 6.8%, respectively).1

Fewer men needed prostate surgery in the combination treatment group than in the dutasteride or tamsulosin monotherapy groups (2.4% vs 3.5% vs 7.8%, respectively).1 Sexual adverse effects occurred in up to 10% of men taking dutasteride with tamsulosin.1,2

Areas of uncertainty

Dutasteride with tamsulosin has not been directly compared with other combination pharmacotherapies for benign prostatic hyperplasia (BPH).

There is insufficient information to assess whether dutasteride prevents prostate cancer.

The relationship between long-term use of dutasteride and male breast cancer is currently unknown.

What does NPS say?

Dutasteride (prescribed with an alpha blocker) is the only 5-alpha reductase inhibitor PBS listed for treating symptomatic BPH.

Combination treatment is more effective than monotherapy, and should be considered for men with enlarged prostates who have moderate or severe symptoms who are at increased risk of disease progression.

Sexual adverse effects are common with dutasteride monotherapy and combination therapy.

PBS listing

Authority required (streamlined)

Dutasteride, and the fixed-dose combination of dutasteride with tamsulosin, are PBS listed for treating lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). Under the listing, dutasteride must be prescribed in combination with an alpha blocker. In both cases treatment must be initiated by a urologist but can be continued by a general practitioner.

May be prescribed by nurse practitioners (continuing therapy only)

Authorised nurse practitioners may prescribe both dutasteride (together with an alpha blocker), and dutasteride-with-tamsulosin fixed-dose combination as continuing therapy, after treatment has been initiated by a medical practitioner. See the PBS website for more information on nurse practitioner PBS prescribing.

What is it?

Dutasteride

Dutasteride is a 5-alpha reductase inhibitor (5-ARI). 5-Alpha reductase (5-AR) converts testosterone into dihydrotestosterone (DHT), and DHT stimulates prostate tissue proliferation. Inhibiting 5-AR reduces prostate size, resulting in improved urinary flow, and prevents progression of BPH in the longer term.3–5

Prostate volume starts to decrease from 1 month after starting dutasteride; maximum effect on symptoms and prostate size can take up to 6–12 months.6,7 Serum prostate specific antigen (PSA) levels are reduced by up to 50% after 6–12 months of dutasteride treatment, even if prostate cancer is present.8

Dutasteride inhibits the action of both isoforms of 5-alpha reductase (type I and type II), while finasteride (also a 5-ARI) is selective for the type II enzyme isoform only.9 However, the clinical relevance of dual inhibition is unknown.7,10–13

Tamsulosin

Tamsulosin is an alpha blocker (specifically an alpha1a-adrenoreceptor antagonist). It relaxes the smooth muscle of the prostate and bladder neck, thereby improving urinary flow. Alpha blockers provide symptomatic relief within 48 hours, with maximum effect in 4–6 weeks, but do not reduce prostate size, or prevent BPH progression.3,14,15

Who is it for?

Dutasteride monotherapy, and dutasteride-with-tamsulosin fixed-dose combination, are indicated for treating men with symptomatic BPH and an enlarged prostate.7,16 Consider dutasteride-with-tamsulosin combination therapy for men ≥ 50 years who are at increased risk of disease progression (prostate volume >30 mL, PSA >= 1.5 ng/mL, International Prostate Symptom Score [IPSS] ≥ 12: see www.cpcn.org/ipss.pdf for the questionnaire).1,2,17–19/p>

Where does it fit?

Combination therapy for enlarged prostate with moderate or severe symptoms

A 5-ARI (dutasteride or finasteride), alone or in combination with an alpha blocker, is recommended for men with moderate or severe urinary symptoms, a prostate volume > 30 mL and PSA > 1.4 ng/mL, who are considered at increased risk of disease progression and who require long-term treatment.11,20,21 However, combination therapy is more effective than monotherapy in reducing prostate size, improving symptoms and urinary flow, and preventing disease progression.1–3,19,22

Watchful waiting or alpha blockers alone for men without enlarged prostates

Watchful waiting (including education, bladder training, lifestyle modifications and regular monitoring) is recommended for men with BPH who have a prostate volume < 30 mL and mild symptoms (IPSS ≤ 7), and those who tolerate moderate symptoms well.11,21,23,24

Alpha blockers are a first-line therapy for men with prostate volume < 30 mL and moderate or severe urinary symptoms (IPSS ≥ 7).11,20,21,24,25 Alpha blockers relax the smooth muscle of the prostate and bladder neck, thereby improving urinary flow. They provide symptomatic relief within 48 hours with maximum effect in 4–6 weeks, but do not reduce prostate size,or prevent BPH progression.3,14,15

Tamsulosin, alfuzosin, prazosin and terazosin are available in Australia. Prazosin is currently the only PBS-listed alpha blocker; tamsulosin and terazosin are available on the Repatriation Pharmaceutical Benefits Scheme (RPBS).26 Alfuzosin is available on private prescription.

Tamsulosin has a similar efficacy to other alpha blockers in improving symptoms and urinary flow.27 Alpha blockers have different side effects that include dizziness, abnormal ejaculation, orthostatic hypotension and asthenia.11,27 Tamsulosin and alfuzosin may be better tolerated than prazosin or terazosin.27,28

How does it compare?

Dutasteride and finasteride have similar efficacy and safety profiles

Data from one head-to-head trial comparing dutasteride (0.5 mg daily) with finasteride (5 mg daily) in men ≥ 50 years with symptomatic BPH (prostate volume ≥ 30 mL, PSA 1.5–10 ng/mL) found no significant difference between the two treatments in symptom scores, prostate volume or urinary flow at 1 year.29–31 Dutasteride and finasteride also have similar safety profiles, with no significant differences in sexual adverse effects.9,29–31 Finasteride is available on the RPBS.

Dutasteride improves urinary flow

Compared with placebo, dutasteride (0.5 mg/day) significantly reduced prostate volume (+1.7% vs –25.7%, respectively), and increased urinary flow from 1 month and symptoms from 6 months onwards, in men 50 years or older with an enlarged prostate and symptomatic BPH (Table 1).2,18

Dutasteride prevents BPH progression

Dutasteride reduced the absolute risk of urinary retention by 2.4% and the need for prostate surgery by 1.9% compared with placebo at 2 years (Table 1).2,18

Table 1.
Effect of dutasteride monotherapy on urinary flow and BPH disease progression at 2 years2

Outcome (mean change from base line)

Dutasteride (n = 2167)

Placebo (n = 2158)

Urinary flow (mL/s)

2.2 ± 5.2*

0.6 ± 4.7

Urinary retention

1.8%*

4.2%

Prostate surgery

2.2%*

4.1%

* Significantly different compared with placebo: p < 0.001; s = second

Combination therapy improves urinary flow

In men > 50 years with an enlarged prostate and symptomatic BPH, 0.5 mg dutasteride co-administered daily with 0.4 mg tamsulosin significantly reduced prostate volume (–27.3%) compared with tamsulosin monotherapy (+4.6%), and increased urinary flow compared with dutasteride monotherapy or tamsulosin monotherapy at 4 years (Table 2).1,17,19


† Responders defined as an increase in urinary flow of 3 mL/s or more from baseline.

Combination therapy prevents BPH progression

Dutasteride co-administered with tamsulosin significantly reduced the incidence of urinary retention and the number of men who required prostate surgery, compared with tamsulosin alone, at 4 years (Table 2).1

Table 2.
Effect of combination therapy on urinary flow and BPH progression at 4 years1

Outcome (mean change from baseline)

Combination
(n = 1610)

Dutasteride
(statistical comparison with combination treatment; n = 1623)

Tamsulosin
(statistical comparison with combination treatment;
n = 1611)

Urinary flow (mL/s)

2.4 mL/s

2.0 mL/s (p = 0.05)

0.7 mL/s (p < 0.001)

Urinary retention

2.2%

2.7% (p = 0.37)

6.8%
(p<0.001)

Prostate surgery

2.4%

3.5% (p = 0.074)

7.8%
(p < 0.001)

Safety issues

Common adverse effects with dutasteride, and dutasteride co-administered with tamsulosin, include dizziness, erectile dysfunction, ejaculation disorders, loss of libido, and gynaecomastia (Tables 3 and 4).1,2,30

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Sexual adverse effects are common with dutasteride and with combination therapy

Impotence, erectile dysfunction, decreased libido, ejaculation disorders and gynaecomastia occur significantly more frequently with dutasteride compared with placebo in the first year of treatment, but not at 2 years (Table 3).2,30 Apart from gynaecomastia, most sexual adverse effects resolved with ongoing therapy.

More men taking dutasteride with tamsulosin had impotence, erectile dysfunction, decreased libido and ejaculation disorders compared with both dutasteride and tamsulosin alone at 2 and 4 years (Table 4).1,2,6,30

Table 3.
Sexual adverse effects with dutasteride monotherapy at 1 year2

Adverse effect

Dutasteride (n = 2167)

Placebo (p value for the comparison
with dutasteride; n = 2158)

Erectile dysfunction

6.0%

3.0% (p < 0.001)

Ejaculation disorders

1.8%

0.7% (p < 0.001)

Decreased libido

3.7%

1.9% (p < 0.001)

Gynaecomastia

1.3%

0.5% (p = 0.009)


Table 4.
Sexual adverse effects with combination treatment at 4 years1

Adverse effect

Combination (n = 1610)

Dutasteride (n = 1623)

Tamsulosin (n = 1611)

Erectile dysfunction

9%

7%

5%

Ejaculation failure

3%

< 1%

< 1%

Retrograde ejaculation

4%

< 1%

1%

Decreased libido

4%

3%

2%

Gynaecomastia

2%

2%

< 1%

‡ There were no statistically significant differences between combination treatment and dutasteride or tamsulosin monotherapy for any of the sexual adverse events reported.

Monitor PSA levels to assess adherence and prostate cancer risk

Serum PSA is used as a surrogate marker of BPH disease progression and prostate cancer.8 Dutasteride and other 5-ARIs reduce serum PSA levels by up to 50% after 6–12 months of treatment, even if prostate cancer is present.8 It is therefore important to measure serum PSA levels at 6–12 months after starting dutasteride or combination treatment to establish a new baseline. In order to compare treatment PSA levels with normal (untreated) ranges, multiply the measured serum PSA value by 2 for men who have taken dutasteride or combination treatment for more than 6 months.29 Investigate any sustained PSA increases from new treatment baseline to rule out non-adherence, and consider biopsy to rule out prostate cancer.7,8

CYP3A4 inhibitors may increase blood concentrations of dutasteride

Dutasteride is metabolised by CYP3A4. Concentrations of dutasteride in blood may therefore increase when taken with the CYP3A4 inhibitors verapamil, diltiazem, ritonavir, ketoconazole, cimetidine and ciprofloxacin; however, this effect is not expected to be clinically significant and therefore no dose adjustment is considered necessary.7

There are no drug interaction studies for dutasteride combination treatment.16

Men taking tamsulosin should inform their ophthalmologist before having cataract surgery

Intra-operative floppy iris syndrome has been observed in some men undergoing cataract surgery who were taking, or who had recently taken, tamsulosin or combination medicines that include tamsulosin.32 The optimal length of time and effects of discontinuing tamsulosin before cataract surgery have not been established.16

Dutasteride may inhibit genital organ development in a male foetus

Dutasteride can be absorbed through the skin. Women who are pregnant or who may become pregnant, children and adolescents should not handle leaking capsules or tablets, as suppressing circulating levels of DHT may inhibit genital organ development.7,16,33 Using a condom is recommended if the man's sexual partner is pregnant or likely to become pregnant, as dutasteride is excreted in semen.7

5-Alpha reductase inhibitors and potential risk of breast cancer

Male breast cancer is rare — the annual incidence in Australia is one case per 100,000 men.34,35 While it is not clear if 5-ARIs do cause breast cancer in men, a safety review by the UK's Medicine and Healthcare products Regulatory Agency of case reports from clinical trials and post-marketing data concluded that an increased risk of breast cancer with finasteride could not be excluded.3,36,37

The relationship between long-term use of dutasteride and male breast cancer is currently unknown. In the clinical trials comparing dutasteride monotherapy with placebo (3374 men), two cases of breast cancer were reported with dutasteride and one in the placebo group.16 In the trial comparing dutasteride with tamsulosin versus dutasteride monotherapy, there were no cases of breast cancer at 4 years.1

Phosphodiesterase type 5 (PDE-5) inhibitors are not contraindicated

While there have been no formal drug interaction studies to evaluate the concurrent use of dutasteride and phosphodiesterase type 5 inhibitors such as vardenafil, sildenafil or tadalafil, they are not contraindicated in men taking dutasteride or the combination with tamsulosin.

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended listing dutasteride on the basis of acceptable cost-effectiveness compared with an alpha blocker alone. The PBAC recommended listing dutasteride-with-tamsulosin fixed-dose combination on a cost-minimisation basis — that is, similar efficacy and cost — compared with a combination of dutasteride and prazosin. The equi-effective doses for these comparisons were (i) dutasteride 0.5 mg and tamsulosin 0.4 mg once daily and (ii) dutasteride 0.5 mg once daily and prazosin 2 mg twice daily.

Dosing issues

The recommended dose of dutasteride is one 0.5 mg capsule, taken orally, once daily at the same time each day, with or without food.

Dutasteride with tamsulosin is taken orally, once daily, as one fixed-dose capsule containing 0.5 mg dutasteride with 0.4 mg tamsulosin hydrochloride, about 30 minutes after a meal at the same time each day.

For both dutasteride and the combination, capsules must be swallowed whole, as the contents can irritate the mouth and throat if chewed or opened.7,16

Avoid dutasteride in men with severe liver impairment

Dutasteride is metabolised by the liver. Avoid dutasteride and dutasteride combination treatment in men with severe liver impairment and be cautious about starting dutasteride or combination treatment in men with mild or moderate liver impairment, as they have not been studied in these groups.7,16

Dose adjustment is not necessary in renal impairment

While dutasteride with tamsulosin has not been studied in men with renal impairment, less than 0.1% of a 0.5 mg steady-state dose of dutasteride is recovered in urine, so no dose adjustment is thought to be required.7

Information for patients

Provide patients and carers with the following information about dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)7,16:

  • take one capsule at the same time each day. Swallow the capsule whole with water and do not chew or open the capsule.
  • treatment is usually long term and symptoms may take 48 hours to improve with combination therapy or 3–6 months to improve with dutasteride monotherapy.
  • sexual adverse effects and dizziness are common.
  • seek medical attention if there are any changes in breast tissue (such as lumps, pain or nipple discharge).
  • women who are, or who may be, pregnant should avoid handling dutasteride capsules, as dutasteride can be absorbed through the skin and may cause birth defects.
  • a condom should be used during sex if your sexual partner is pregnant or likely to become pregnant.
  • defer donating blood until 6 months after stopping treatment to avoid the possibility of transmitting dutasteride to pregnant women.

Discuss the Avodart or Duodart consumer medicine information (CMI) leaflet with the patient.

Revision history

Updated August 2011 to include information on the PBS listing of dutasteride-with-tamsulosin fixed-dose combination.

First published April 2011.

References

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