Dutasteride Capsules (Avodart®) Plus Tamsulosin (Flomax®) for BPH
Pharmacology Update
Dutasteride Capsules (Avodart®) Plus Tamsulosin (Flomax®) for BPH
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The FDA has approved the combination of dutasteride and tamsulosin for the treatment of symptomatic enlarged prostate. Dutasteride is a 5-alpha reductase inhibitor that reduces prostate volume by blocking the conversion of testosterone to dihydrotestosterone leading to epithelial atrophy. Tamsulosin is an alpha-adrenergic receptor blocker that reduces smooth muscle tone in the prostate and bladder neck. Both products have been previously approved as monotherapy for benign prostatic hyperplasia.
Indications
Dutasteride is indicated for use in combination with tamsulosin for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with enlarged prostate.1
Dosage
The recommended dose is dutasteride 0.5 mg once daily with tamsulosin 0.4 mg daily. Tamsulosin should be taken 30 minutes after the same meal every day.
Potential Advantages
The combination provides greater benefit than monotherapy with tamsulosin or dutasteride alone in improving urinary symptoms, quality of life, and peak urinary flow in men with symptomatic BPH.1,2
Potential Disadvantages
The combination also combines the adverse events of both agents. Sexual dysfunction (eg, erectile dysfunction, impotence, decreased libido, ejaculation disorder) and nipple pain have been associated with dutasteride.1,2 Orthostatic hypotension, headache, and dizziness have been associated with tamsulosin.
Comments
The approval of combination therapy was based on the 2-year results of an ongoing study, Combination of Avodart and Tamsulosin (CombAT).1,2,3 This 4-year, double-blind, multicenter study enrolled 4838 male subjects 50 years of age and older, with moderate-to-severe symptoms, with prostate volume of 30 cm3 or larger, and PSA of 1.5 ng/ml or higher. Subjects were randomized to tamsulosin (0.4 mg), dutasteride (0.5 mg), or the combination once daily. The primary endpoint was change in the International Prostate Symptom Score (IPSS). This is identical to the American Urological Association Symptom Index (AUA-SI) with the addition of a quality of life question. The 4-year endpoints were timed to BPH-related surgery or acute urinary retention. Secondary endpoints included change in prostate volume and peak urinary flow. At 2 years, the combination showed a significant improvement of IPSS over dutasteride (after 3 months) and tamsulosin (after 9 months) and improvement in BPH-related quality of life (after 3 and 12 months respectively) as well as improved peak urinary flow from baseline (after 6 months).
Adverse events were more frequent in the combination regimen. CombAT is the second large study involving a 5-alpha-reductase inhibitor with an alpha-adrenergic blocker. The Medical Therapy of Prostate Symptoms (MTOP) trial randomized 3047 male subjects to finasteride, doxazosin, and the combination.4 That study concluded that the combination was more effective in reducing the risk of composite clinical progression (eg, ³4 point increase in AUA-SI, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or urinary incontinence). However, the difference between the combination and doxazosin in terms of symptoms was not statistically significant at 1 year.4 The findings also suggest that men with larger prostates and higher PSA gained more benefit. In CombAT, the subjects had larger prostate volume (mean of 55 ± 23.4 cm3 vs 36.3 ± 20.1 cm3) and higher PSA value (4.0 ± 2.06 ng/ml vs 2.4 2.1 ng/ml). It is not known if the combination of any 5-alpha reductase inhibitor and any alpha-adrenergic receptor blockers would achieve the same therapeutic effect. Dutasteride is an inhibitor of type 1 and type 2 while finasteride inhibits type 2 isoenzyme only. Similar prostate volume reduction has been reported with the two drugs.5 Compared to other alpha-blockers tamsulosin and alfuzosin are more selective for the receptors in the genitourinary tract.
Clinical Implications
The combination of dutasteride and tamsulosin has been shown to benefit patients with larger prostate volume and higher PSA levels. Currently, the American Urological Associate recommends combination therapy for men with symptoms and demonstrably enlarged prostate glands.6
References
1. Avodart Product Information. GlaxoSmithKline. June 2008.
2. Roehrborn CG, et al. J Urol. 2008;179(2):616-621.
3. Sianmi P, et al. Contemp Clin Trial. 2007;28(6):770-779.
4. McConnell JD, et al. N Engl J Med. 2003;349:2387-2398.
5. Nickel JC. Rev Urol. 2004;6 (suppl 9):S331-S339.
6. http://www.auanet.org/guidelines/bph.cfm accessed 7/4/08
The FDA has approved the combination of dutasteride and tamsulosin for the treatment of symptomatic enlarged prostate.Subscribe Now for Access
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