Dutasteride Capsules (Avodart—GlaxoSmithKline)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
GlaxoSmithKline is expected to launch a new drug for benign prostatic hypertrophy (BPH) in December. Dutasteride is a 5 alpha-reductase inhibitor, which was previously approved in November 2001 but not launched. In October 2002, a supplemental labeling was approved to include 2-year data on acute urinary retention and need for surgery. Dutasteride is similar to finasteride (Proscar), but unlike the older drug, dutasteride inhibits both 5-alpha reductase inhibitor isoforms (type 1 and type 2). This enzyme converts testosterone to dihydrotestosterone, which is responsible for the enlargement of the prostate. GlaxoSmithKline will market dutasteride as Avodart.
Dutasteride is indicated for the treatment of symptoms of BPH in men.1
The recommended dose is 0.5 mg once daily. It may be taken without regard to meals. Dutasteride is available as 0.5 mg capsules.
Dutasteride inhibits both type 1 and type 2 5-alpha reductase. More complete inhibition of conversion from testosterone to DHT is achieved with this dual inhibition. In a placebo-controlled study, 90.2% reduction was achieved with dutasteride compared to +9.6% for placebo.2 In contrast, approximately 70% reduction has been reported for finasteride.3
A small percent of subjects reported sexual adverse effects. These include decreased libido (4% vs 2% for placebo), impotence (7% vs 4%), ejaculation disorder (2% vs < 1%), and gynecomastia (1% vs < 1%).4 Symptomatic relief of BPH generally requires 3-6 months of therapy.2 The drug has not been well studied in non-Caucasian populations. In the phase III trial 91% of the studied subject who received the dutasteride were Caucasian. Only 4% were African Americans, 3% were Hispanic, and 1% were Asian.4 Due to the long elimination half-life of dutasteride (about 5 weeks), the patients should not donate blood for at least 6 months after discontinuation of dutasteride. Women who are pregnant or who may become pregnant should not handle the capsules. Dutasteride reduces PSA levels by 40-50%.
Dutasteride is the second 5-alpha reductase inhibitor. It inhibits not only the dominant form (type 2) found in the prostate but also type 1 found in the liver and skin. Data supporting the efficacy and safety of dutasteride were based on three 24-month placebo-controlled studies. The combined trials included 4325 subjects (2951 completed) with moderate-to-severe symptoms, a peak urinary flow rate of 15 mL/sec or less, prostate volume of 30 cm3 or greater, and PSA of 1.5-10.0 ng/m.2 The primary efficacy end points were the change from baseline in American Urological Association-Symptom index score (AUASI) and risk of acute urinary retention. AUASI is a self-administered questionnaire that addressed urinary symptoms such as incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Dutasteride showed a 21.4% improvement in AUASI and 57% reduction of acute urinary retention. Secondary end points included peak urinary flow rate, reduction in total prostate volume, and risk of benign prostate hyperplasia-related surgical intervention. Peak urinary flow rate increased by 2.2 mL/sec, prostate volume was reduced by 25.7%, and surgical intervention reduced by 48%. All these end points were statistically different from placebo treatment. These findings are similar to those reported for finasteride in a 4-year study.5 Patients with prostate volume > 40 cm3 appeared to benefit more compared to those with prostate volume < 40 cm3. Improvement in peak urinary flow rate was regarded as modest.4 The cost of dutasteride was not available at the time the review was prepared.
The dual inhibitory effects on the 2 isoforms provide greater reduction in DHT than finasteride. However, it is not clear if this translated into better clinical outcomes. Currently there are no comparative studies between the two 5-alpha reductase inhibitors and no comparative studies between dutasteride and an alpha-1 adrenergic antagonist (ie, terazosin doxazosin, tamsulosin). Current evidence indicates that alpha-1 adrenergic antagonists are more effective than finasteride.6,7 In addition their effectiveness does not appear to be dependant on prostate size. In patients with enlarged prostates, a 5 alpha-reductase inhibitor may be considered. The benefit of combination therapy with an alpha-antagonist and 5-alpha reductase inhibitor had not been established.6 However, results from a NIH study (the Medical Therapy of Prostatic Symptoms [MTOTS]) recently reported at the American Urological Association indicated that the combination of finasteride and doxazosin was more effective than each drug alone in the slowing BPH progression.8 Progression was defined as significant worsening of symptoms, recurring urinary tract infection, urinary retention, incontinence, or surgery. The risk of progression was reduced by 67% with the combination, 39% with doxazosin and 34% with finasteride.
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. Both are Associate Editors of Internal Medicine Alert.
1. Advodart Product Information. GlaxoSmithKline. October 2002.
2. Roehrborn CG, et al. Urology. 2002;60:434-441.
3. Gormley GJ, et al. N Engl J Med. 1992;327:1185-1191.
4. Center for Drug Evaluation and Research. Dutasteride Medical Review.
5. McConnell JD, et al. N Engl J Med. 1998;338:557-563.
6. Lepor H, et al. N Engl J Med. 1996;335(9):533-539.
7. Wilt TJ, et al. BJU Int. 2002;89(3):214-225.
8. NIH News Release. http://nih.gov/news/pr/may2002/niddk-28.htm.