Dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)

NPS RADAR | AUGUST 2011

Dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)

for lower urinary tract symptoms due to benign prostatic hyperplasia
(dew-TAS-ta-ride, tam-zu-LOW-sin)

Effective for enlarged prostate and moderate or 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 612 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 adherence 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 46 months after stopping treatment.

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 (www.pbs.gov.au/browse/nurse) for more information on nurse practitioner PBS prescribing.

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Dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)

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EvIDENCE SNAPShot
WhAt is KnoWn About these Drugs AreAs of uncertAinty WhAt Does nps sAy?

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

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.

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.

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.35 Prostate volume starts to decrease from 1 month after starting dutasteride; maximum effect on symptoms and prostate size can take up to 612 months.6,7 Serum prostate specific antigen (PSA) levels are reduced by up to 50% after 612 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.7,1013

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 46 weeks, but do not reduce prostate size, or prevent BPH progression.3,14,15

Who is it for?
Dutasteride monotherapy, and dutasteride-withtamsulosin 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 aged 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).1,2,1719

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Dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)

NPS RADAR | AUGUST 2011

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 to 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.13,19,22 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 46 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
Table 1.

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 1.510 ng/mL) found no significant difference between the two treatments in symptom scores, prostate volume or urinary flow at 1 year. 2931 Dutasteride and finasteride also have similar safety profiles, with no significant differences in sexual adverse effects.9,2931 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 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

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

outcome (mean change from baseline) Urinary flow (mL/s) Urinary retention Prostate surgery

Dutasteride (n = 2167) 2.2 5.2* 1.8%* 2.2%*

Placebo (n = 2158) 0.6 4.7 4.2% 4.1%

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

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Table 2.

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

outcome (mean change from baseline) Urinary flow (mL/s) Urinary retention Prostate surgery

Combination (n = 1610) 2.4 mL/s 2.2% 2.4%

Dutasteride (statistical comparison tamsulosin with combination treatment; n = 1623) (n = 1611) 2.0 mL/s (p = 0.05) 2.7% (p = 0.37) 3.5% (p = 0.074) 0.7 mL/s (p < 0.001) 6.8% (p < 0.001) 7.8% (p < 0.001)

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

Safety issues
Common adverse effects with dutasteride, and dutasteride co-adminstered 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 (www.ebs.tga.gov.au) or by using the Blue Card distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website (www.tga.gov.au).

Table 3.

Sexual adverse effects with dutasteride monotherapy at 1 year2

Adverse effect Erectile dysfunction Ejaculation disorders Decreased libido Gynaecomastia

Dutasteride (n = 2167) 6.0% 1.8% 3.7% 1.3%

Placebo (p value for the comparison with dutasteride; n = 2158) 3.0% (p <0.001) 0.7% (p <0.001) 1.9% (p <0.001) 0.5% (p = 0.009)

Table 4.

Sexual adverse effects with combination treatment at 4 years1

Adverse effect* Erectile dysfunction Ejaculation failure Retrograde ejaculation Decreased libido Gynaecomastia

Combination (n = 1610) 9% 3% 4% 4% 2%

Dutasteride (n = 1623) 7% <1% <1% 3% 2%

tamsulosin (n = 1611) 5% <1% 1% 2% <1%

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

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Dutasteride (Avodart) and dutasteride with tamsulosin (Duodart)

NPS RADAR | AUGUST 2011

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 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 612 months of treatment, even if prostate cancer is present.8 It is therefore important to measure serum PSA levels at 612 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 nonadherence, 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 mans 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 UKs 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 inhibitors (pDe-5) 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.7,16

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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.

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 36 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.

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 dutasteride 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 Whilst 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

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REfERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Roehrborn CG, et al. Eur Urol 2010;57:12331. Roehrborn CG, et al. Urology 2002;60:43441. McConnell JD, et al. N Engl J Med 2003;349:238798. Barkin J, et al. BJU Int 2009;103:91926. Miller J, Tarter TH. Clin Interv Aging 2009;4:2518. Naslund M, et al. Am J Manag Care 2008;14:S14853. GlaxoSmithKline Australia Pty Limited. Product Information. Avodart soft capsules, 24 February 2009. Gravas S, Oelke M. World J Urol;28:915. Clark RV, et al. J Clin Endocrinol Metab 2004;89:217984. Merk Sharp & Dohme (Australia) Pty Limited. Product Information. Proscar (finasteride), 11 May 2004. European Association of Urology. Guidelines on conservative treatment of non-neurogenic male LUTS. 2010. http://www.uroweb.org/gls/pdf/ BPH%202010.pdf (accessed 16 December 2010). Montorsi F, et al. Prostate 2009;69:895907. Andriole G, et al. J Urol 2004;172:1399403. Hartung R. Eur Urol 2001;39 Suppl 6:138. Roehrborn CG. Prostate Cancer Prostatic Dis 2006;9:1215. GlaxoSmithKline Australia Pty Limited. Product Information. Duodart 500 g/400 g, 20 October 2010. Siami P, et al. Contemp Clin Trials 2007;28:7709. Debruyne F, et al. Eur Urol 2004;46:48894. 19. Roehrborn CG, et al. J Urol 2008;179:61621.

20. National Institute for Health and Clinical Excellence. Lower urinary tract symptoms. The management of lower urinary tract symptoms in men. NICE clinical guideline 97, Issue date: May 2010. 21. Andrology Australia. Prostate Disease. BPH and prostatitis diagnosis and management. Clinical Summary Guide 7. May 2010. http://www. andrologyaustralia.org/docs/clinical-summaryguide07_May2010.pdf (accessed 4 January 2011). Abrams P, et al. J Urol 2009;181:177987.

22. Ravish IR, et al. Arch Androl 2007;53:1720. 23. American Urological Association. Management of BPH clinical guideline. 2003. Updated 2006. http://www.auanet.org/content/guidelines-andquality-care/clinical-guidelines.cfm?sub=bph (accessed 16 December 2010). 24. Abrams P, et al. J Urol 2009;181:177987. 25. Fitzpatrick JM, Kirby RS. BJU Int 2006;97 Suppl 2:1620. 26. Australian Department of Health and Ageing. Schedule of Pharmaceutical Benefits. 1 January 2011. http://www.pbs.gov.au/pbs/home (accessed 7 January 2011). 27. Wilt TJ, et al. Cochrane Database Syst Rev 2003:CD002081.

12. 13. 14. 15. 16. 17. 18.

28. Australian Medicines Handbook 2010. 29. Nickel JC. Rev Urol 2004;6 Suppl 9:S319. 30. Andriole GL, Kirby R. Eur Urol 2003;44:828.

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REfERENCES Continued
31. GlaxoSmithKline. Clinical Trial Report: Study ARI40001 Year 1. A multicentre, randomised, double blind, double dummy parallel-group study to compare the efficacy of dutasteride/GI198745 0.5mg od versus finasteride 5mg od for 12 months in the treatment of subjects with benign prostatic hyperplasia (BPH), followed by an optional 24 months open label phase, 22 December 2004. http://download.gsk-clinicalstudyregister.com/ files/914.pdf (accessed 16 December 2010). Chang DF, Campbell JR. J Cataract Refract Surg 2005;31:66473. 36. Medicines and Healthcare products Regulatory Agency. MHRA Public Assessment Report. The risk of breast cancer with finasteride. 2009. http://www.mhra.gov. uk/Safetyinformation/Safetywarningsalertsandrecalls/ Safetywarningsandmessagesformedicines/ CON065479 (accessed 16 December 2010). 37. Medicines and Healthcare products Regulatory Agency. Drug safety update: Volume 3 Issue 5. Finasteride: potential risk of male breast cancer. December 2009. http://www.mhra.gov.uk/ Publications/Safetyguidance/DrugSafetyUpdate/ CON065444 (accessed 16 December 2010).

32.

33. Med Lett Drugs Ther 2008;50:7980. 34. Sasco AJ, et al. Int J Cancer 1993;53:53849. 35. Australian Cancer Database. Australian Institute of Health and Welfare. http://www.aihw.gov.au/cancer/data/ datacubes/index.cfm (accessed 16 December 2010).

38. GlaxoSmithKline. Avodart (dutasteride). Consumer Medicine Information. Issue No.4. 19 December 2008.

Updated August 2011 to include information on the PBS listing of dutasteride-with-tamsulosin fixed-dose combination. First published: April 2011 The information contained in NPS RADAR is derived from a critical analysis of a wide range of authoritative evidence and is current at the time of publication. Any treatment decisions based on the information provided in NPS RADAR should be made in the context of the clinical circumstances of each patient.

NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory or PBS listing changes.
Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information.

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